NO130825B - - Google Patents

Description

Analogous process for the production of benzenesulfonylurea derivatives with blood sugar-lowering action.

This invention relates to an analogous process for the production of new benzenesulfonylureas with the general one

formula:

where R"*" means n-butyl, isobutyl, cyclohexenyl, cycloalkyl with 5-8 ring carbon atoms, 2,5-endomethylene-cyclohexyl, endoethylenecyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl or ;4-me toc sy cyclohexyl, ;R 2 means hydrogen, or methyl, methoxy, bromine or chlorine in the p- or preferably in the m-position to the CONH group of the benzene ring, R 3 and R 4 can be the same or different and means hydrogen or methyl, and A means the chain of 2 -4 carbon atoms that complete a benzofuran, dihydrobenzofuran, chromane, 2H-chromene or homochromane ring system, or salts thereof with bases. ;The new sulfonylurea compounds with the above formula and salts thereof are prepared according to the invention by (a) that a p-acylamidoethylbenzenesulfonamide with the formula: ;2 3 4 where A, R , R and R have the above meanings, or a salt thereof, is reacted with a compound of the formula R^-Z, where R- has the meaning given above, and where Z means an isocyanate residue, a carbamide ester residue, a thiolcarbamide ester residue, a carbamide halide residue, a hydrocarbon-substituted or an unsubstituted urea residue, an acylurea residue or a nitrourea residue, or by reacting a salt of the above sulfonamide with an amine of the formula R^NH2, where R^" has the above meaning, in the presence of N,N<1->carbonyldiimidazole, or (b) that a compound of the formula ; where A, R<2>, R<3> and R<4> have the meanings given above, and X1 means an isocyanate residue, a carbamide acid ester residue, a carbamide acid halide residue, a thiolcarbamide acid ester residue, a hydrocarbon substituted or u substituted urea residue, an acylurea residue, a semicarbazide residue, a semicarbazone residue or imino-1,3-oxathiolane, is reacted with an amine R1NH2 where R has the above meaning, or a salt thereof, or (c) that the group ;2 3 4 where A , R , R and R have the meanings given above, are introduced in one or more steps by acylation of a p-aminoalkyl-benzene-sulfonylurea with the formula: where R"*" has the meaning given above or (d) that in the presence of a catalyst hydrogenates a benzenesulfonylurea of the formula

where R° means an unsaturated group, which in the process is converted into a saturated R^ group, including in particular cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl,

2 2,5-endomethylenecyclohexyl or endoethylenecyclohexyl and A, R ,

3 4

R and R have the meanings given above or

(e) that one hydrolyzes a compound of the formula

or or 12 3 4 where A, R R , R and R have the meanings given above and T means halogen, preferably chlorine, the remaining part of an isourea ether or the remaining part of an isothiourea ether, or (f) that one, in particular by treatment with oxidizing agents or by treatment with oxides or salts of metal, exchange sulfur with oxygen in a compound of the formula or or 12 3 4 where A, R , R , R and R have the above meanings, or (g) that one adds water to a benzenesulfonyl carbodiimide with the formula 12 3 4 where A, R , R , R and R have the meanings given above, or (h) that one reacts a p-acylamidoalkylbenzenesulfonyl halide with the formula

3 4 2'

where A, R and R have the meanings given above, R means chlorine, bromine or methyl and X means halogen, preferably chlorine, with an alkali metal salt of a urea f of the formula ^NCONH-R"^", where R^" has the above meanings,

after which the thus produced benzenesulfonylureas are optionally converted into physiologically acceptable salts, preferably alkali metal salts, by treatment with bases.

The methods described above are all known,

in a different context, and most of these methods are recognized as standard methods for the production of benzene-sulfonylureas.

The new sulfonylurea compounds with the above general formula exhibit as such or in the form of salts a strong blood sugar-lowering effect after oral administration and are thus useful for the production of pharmaceutical preparations for the oral treatment of diabetes mellitus.

The new benzenesulfonylureas with the above general formula differ from the previously known, analogous compounds in the structure of the acylamido groups used in the para-substituent of the benzene ring with the general formula

2 3 4

where A, R , R and R have the meanings given above- Each of these groups is derived from one of the bicyclic ring systems mentioned above, all of which contain an oxygen atom in the ring. The introduction of these ring systems according to the invention has led to compounds with a surprisingly better effect than the previously known analogous compounds containing other bicyclic acylamido groups.

The hypoglycemic effect of the new compounds has been demonstrated by oral administration of solutions of their sodium salts to fasted rabbits, followed by repeated determinations of the animals' blood glucose concentrations over the following 24 hours.

Table I shows the blood sugar-lowering effect for a number of the new compounds.

For comparison, table II lists the blood sugar-lowering effect for the following previously known benzenesulfonylureas:

Compound A is described in Danish patent 118,553

(Example 1) together with a number of benzenesulfonylureas of a similar structure. These compounds all contain a bicyclic acylamido group in the para-substituent, and the bicyclic ring systems contained herein are made up exclusively of carbon atoms.

Compound B is described in Danish patent 119,052

(Example 53). This compound is one of the few known benzenesulfonylureas whose para-substituent contains an acylamido group derived from a bicyclic ring system containing two oxygen atoms in the ring.

Compound C is "Tolbutamide", which is the most so far

applied ben zen su1fonylur in stof f.

Table in:

Blood sugar-lowering activity expressed as reduction of

the initial blood glucose concentration in rabbits after oral administration of a single dose after 16 hours of fasting. A line

(-) means a value below 10%.

The new benzenesulfonylureas produced according to the invention are distinguished by the fact that they have a much lower acute toxicity than tolbutamide. As an example, compound no. 5 (table I) can be mentioned for which LDr^ > 20000 mg/kg after oral

OE OE

administration of a suspension of finely powdered material to rats and mice, while the LD5Q was found to be 12500 mg/kg by intraperitoneal administration to the same species. Tolbutamide showed LD|-Q = 1500 mg/kg p.o. and LD^q = 800 mg/kg i.p. in mice, and as LD,_0 = 2700 mgAg p.o. and LD5Q = 1200 mgAg i.p. in rats when examined in the same way.

The following examples illustrate the method according to the invention.

Example 1

N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)- N'- cyclohexylurea

4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide (3.7 g) and anhydrous potassium carbonate (3.1 g) are refluxed in acetone ( 50 ml) for 2 hours. A solution of cyclohexyl isocyanate (1.5 g) in acetone (15 ml) is then added and stirring under reflux is continued for a further 16 hours. The reaction mixture is then cooled, and the solids are filtered off and washed with acetone. The moist cake is dissolved in water (100 ml) and acetone (120 ml), and a small amount of insoluble material is filtered off. The filtrate is acidified with dilute hydrochloric acid, and the precipitate is filtered off, washed with water and dried. The yield of the crude product is 4.5 g (90%), m.p. 196-200°C. Recrystallization from dimethylformamide-methanol yields 3.2 g (71% recovery) of pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)- benzenesulfonyl)-N'-cyclohexylurea, m.p. 207-208°C.

The following sulfonylureas are prepared by analogous methods: N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamideq)-ethyl)-benzenesulfonyl)-N1- n- butyl urea, m.p. 148-149°C (methanol),

N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea,

sm.p. 161-162°C (dimethylformamide-methanol),

N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N1 -(4-methylcyclohexyl)-urea, sm. p. 122-124°C (methanol) for the monohydrate, or m.p. 167-168°C. for the anhydrous form,

N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(4,4-dimethylcyclohexyl)-urea , sm.p. 141-143°C (methanol),

N-(4-(2-(2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, m.p. 180-181°C (dimethylformamide-methanol),

N-(4-(2-(2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-n-butylurea, m.p. 125-126 C (acetone-water),

N-(4-(2-(5-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-n-butylurea,

sm.p. 173-174°C (dimethylformamide-methanol),

N-(4-(2-(5-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexyl urea,

sm.p. 184-186°C (dimethylformamide-methanol),

N-(4-(2-(5-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(4-methylcyclohexyl)-urea, sm .p. 113-115°C (n-butyl acetate),

N-(4-(2-(5-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(4,4-dimethylcyclohexyl)-urea , sm.p. 132-135°C (methanol),

N-(4-(2-(4-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl-benzenesulfonyl)-N'-cyclohexylurea,

sm. p. 175-176 C (methanol),

N-(4-(2-(4-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)benzenesulfonyl)-N'-cyclohexylurea,

sm.p. 180-181°C (dimethylformamide-methanol),

N-(4-(2-(5-chloro-2-methylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, m.p. 193-194°C (dimethylformamide-methanol),

N-(4-(2-(2-methylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylurea, m.p. 182-184°C (tetrahydrofuran-acetone),

N-(4-(2-(6-methylchroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N1-(4-methylcyclohexyl)-urea, m.p. 199-200°C (dimethylformamide-methanol),

N-(4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, m.p. 198-199°C (dimethylformamide-methanol),

N-(4-(2-(6-Methoxychroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, m.p. 183-184°C (dimethylformamide-methanol),

N-(4-(2-(chromane-8-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, m.p. 198-199°C (dimethylformamide-methanol),

N-(4-(2-(chromane-8-carboxamido)-ethyl-benzenesulfonyl)-N1 - n-butylurea, m.p. 136-137°C (methanol),

N-(4-(2-(homochroman-9-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylurea, m.p. 201-202°C (dimethylformamide-methanol),

N-(4-(2-(homochroman-9-carboxamido)-ethyl)-benzenesulfonyl)-N<1->(4-methylcyclohexyl)-urea, m.p. 160-161°C (methanol).

The 4-(2-(2,5-dimethyl-2,3-dibydrobenzo[b]furan-7-carboxamido)-ethyl)benzenesulfonamide used as starting material in example 1 is prepared as follows:

2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid

(19.2 g) is refluxed for 2 hours with thionyl chloride (22 ml)

and 2 drops of dimethylformamide. Excess thionyl chloride is removed by vacuum extraction at 60-70°C and water-suction pump-vacuum. The remaining crude acid chloride (21.2 g) is dissolved in acetone (90 ml),

and this solution is added dropwise with stirring to a cooled (0-5°C) solution of 4-(2-aminoethyl)-benzenesulfonamide hydrochloride (21.3 g) in water (180 ml) while keeping the pH value at approx. . 9.8 by simultaneous addition of a 4N sodium hydroxide solution. About-

stirring is continued for 30 minutes after the addition is complete,

and the pH value is then regulated to approx. 7.0. The precipitate is filtered off, washed with water and dried. The yield of crude 4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide is 28.7 g (85%). Recrystallization from dimethylformamide-methanol gives the pure compound with m.p. 199-200°C.

The following sulfonamides are prepared in the same way from

the corresponding carboxylic acids: 4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, m.p. 202-203°C (dimethylformamide-methanol),

4-(2-(2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl<y->benzenesulfonamide, m.p. 176-177°C (dimethylformamide-methanol),

4-(2-(5-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, m.p. 243-244°C (dimethylformamide-methanol),

4-(2-(4-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, m.p. 225-226°C (dimethylformamide-methanol),

4-(2-(4-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, m.p. 208-209°C (dimethylformamide-methanol),

4-(2-(5-chloro-2-methylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, m.p. 215-216°C (dimethylformamide-methanol),

4-(2-(2-methylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, m.p. 184-186°C (acetone-water),

4-(2-(6-methylchroman-8-carboxamido)-ethyl)-benzenesulfonamide, m.p. 215-216°C (dimethylformamide-methanol),

4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfone-

amide, m.p. 221-222°C (dimethylformamide-methanol),

4-(2-(6-Methoxyroman-8-carboxamido)-ethyl)-benzenesulfonamide, m.p. 228-230°C (dimethylformamide-methanol),

4-(2-(chroman-8-carbaxamido)-ethyl)-benzenesulfonamide,

sm.p. 194-195°C (dimethylformamide-methanol) and

4-(2-(homochroman-9-carboxamido)-ethyl)-benzenesulfonamide, m.p. 180-182°C (dimethylformamide-methanol).

The compound 2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid used for the preparation of the above 4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7) -carboxamido)-ethyl)-benzenesulfonamide is produced by the following reaction sequence:

(a) Methyl 2-allyloxy-5-methylbenzoate:

Methyl 5-methyl salicylate (429 g) and anhydrous potassium carbonate (356 g) are stirred and refluxed for 24 hours with allyl bromide (312 g) in acetone (430 ml). About. 400 ml of acetone are then distilled off at atmospheric pressure. The residue is cooled to 25°C, and water (1200 ml) as well as toluene (245 ml) are added. Stirring is continued for a few minutes and the mixture is then allowed to separate. The aqueous phase is discarded, and the toluene solution is dried over anhydrous sodium sulfate. The toluene is stripped off, and the residue is fractionated in vacuo to give 396 g of methyl-2-allyloxy-5-methylbenzoate,

k.p. (10 mm Hg) = 152-154°C.

The following 2-allyloxybenzoic acid esters are prepared on

in the same way from the corresponding salicylic acid esters:

methyl 2-allyloxy-5-methoxybenzoate, m.p. 42-43°C

(hexane), b.p. (0.9 mm Hg) = 123-126°C, methyl 2-allyloxybenzoate, b.p. (12 mm Hg) = 137-138°C,

methyl 2-allyloxy-5-chlorobenzoate, m.p. (3.5 mm Hg) = 140-141°C, methyl 2-allyloxy-4-methoxybenzoate,

k.p. (0.7 mm Hg) = 125-127°C and

methyl 2-allyloxy-4-chlorobenzoate, m.p. 59-60°C (methanol).

(b) Methyl 3-allyl-5-methyl salicylate:

Methyl 2-allyloxy-5-methylbenzoate (175 g) is heated to

245°C in a nitrogen atmosphere. The strongly exothermic Claisen rearrangement then causes a sudden rise in temperature to 285°C. More methyl-2-allyloxy-5-methylbenzoate (220 g) is added over 10 minutes at 275-285°C. The temperature is maintained at this level for a further 30 minutes, after which the reaction mixture is cooled and finally distilled in vacuo to give 326 g (83%) of methyl 3-allyl-5-methylsalicylate, b.p. (llmm Hg) = 144 C.

A modified method in which a mixture of

equal amounts of the allyloxybenzoic acid ester and N-methyl-2-pyrrolidone are refluxed for 2-3 hours, is particularly suitable for the preparation of the 4- and 5-methoxy-substituted compounds listed below, since much lower yields are obtained in these

traps in the absence of a solvent.

The following intermediate products are obtained by the above methods:

Methyl 3-allyl-5-methoxysalicylate,

k.p. (0.9 mm Hg) = 114-117°C,

methyl 3-allyl salicylate,

k.p. (10 mm Hg) = 131-135°C,

methyl 3-allyl-5-chlorosalicylate,

k.p. (0.4 mm Hg) = 104-105°C,

methyl 3-allyl-4-methoxysalicylate,

sm.p. 57-58°C (methanol) and

methyl 3-allyl-4-chlorosalicylate,

k.p. (0.4 mm Hg) = 95-98°C.

(c) 2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid:

Dry hydrogen bromide (approx. 115 g) is slowly bubbled through

a cooled (0-5°C) - and stirred solution of methyl-3-allyl-5.-methylsalicylate (145.6 g) and anhydrous ferric chloride (0.1 g) in chloro-

form (300 ml). Stirring (at approx. 0°C) is continued for 1 hour after completion of the hydrogen bromide addition. The reaction mixture is allowed to stand overnight without cooling. Excess hydrogen bromide and chloroform are then removed by vacuum stripping. The residue (182 g) is dissolved in methanol (200 ml) at 35°C, and this solution is slowly added to a stirred solution of potassium hydroxide (100g) in methanol (400 ml) while the temperature is kept below 35°C by external cooling. Stirring at 25 to 35°C is continued for 15 minutes after the addition, and the reaction mixture is then refluxed for 30 minutes. Methanol is then removed using suction pump vacuum and water (150 ml) is added to dissolve the potassium salts. The solution is filtered and acidified with dilute saline

acid. The crystals are filtered off and washed with water. After drying, 120 g (88%) of impure 2,5-dimethyl-2,3-dihydrobenzo-[b]furan-7-carboxylic acid is obtained, m.p. 140-145°C. Recrystallization from xylene gives the pure acid (90% recovery in the first crystal portion)

with sm.p. 149-150°C.

The following 2,3-dihydrobenzo[b]furan-7-carboxylic acids

are prepared in the same way: 5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid,

sm.p. 123-124°C (n-butyl acetate),

2-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid,

sm.p. 125-127°C (xylene),

5-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid,

sm.p. 190-191°C (acetic acid),

4-Methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid,

sm.p. 208-209°C (acetic acid) and

4-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid,

sm.p. 212-213°C (acetic acid).

The compound 2-methylbenzo[b]furan-7-carboxylic acid is prepared as follows: (a) 2-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid (91 g) and p-toluenesulfonic acid (0.5 g ) is refluxed in methanol (420 ml) for 48 hours. Most of the methanol is then removed in vacuo and the residue (98.6 g) is dissolved in benzene (300 ml). Unesterified carboxylic acid is recovered by extractions from the benzene solution with sodium bicarbonate solution followed by acidification. The benzene is then removed by vacuum stripping to give the methyl ester (89.5 g or 91%) of 2-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid. (b) Crude methyl ester of 2-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid (19.2 g) from (a) is refluxed for 2 hours in carbon tetrachloride (375 ml) with N-bromosuccinimide ( 17.8 g) in the presence of benzoyl peroxide (0.1 g). The reaction mixture is then cooled and succinimide is removed by filtration. The carbon tetrachloride is distilled off in vacuo, and the residue (20.7 g) is dissolved in dimethylformamide. Lithium carbonate (8.2 g) is added and the mixture is stirred under reflux overnight, followed by cooling and filtration. Dimethylformamide is removed by vacuum stripping, and the residue is refluxed for 1 hour with 10% sodium hydroxide solution. The solution is then cooled and acidified. The precipitate is filtered off, washed with water and dried. The yield of impure 2-methylbenzo[b]furan-7-carboxylic acid, m.p. 130-136 C, is 13.7 g (78%). Purified acid with m.p. 140-142°C is obtained from aqueous methanol.

In the same way, the following is produced:

5-chloro-2-methylbenzo[b]furan-7-carboxylic acid, m.p. 229-

232°C (tetrahydrofuran-water).

The compound 6-methylchroman-8-carboxylic acid (6-methyl-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid) required above is prepared by the following course of reaction:

(a) Methyl 3-allyl-5-methyl acetylsalicylate:

A mixture of methyl-3-allyl-5-methylsalicylate (247 g), acetic anhydride (264 ml) and p-toluenesulfonic acid (0.4 g) is refluxed for 19 hours and then cooled to approx. 25°C. Water (700 g) is added and the mixture is extracted twice with toluene (300 ml and 150 ml). The combined toluene extracts are dried over water

free sodium sulfate, and the toluene is then distilled off in vacuum.

The residue is distilled in vacuo to give 253 g (85%) of methyl-3-allyl-5-methyl-acetylsalicylate, b.p. 0.8 mm Hg) = 123-125°C.

In the same way, the following is produced:

methyl 3-allyl-5-chloro-acetylsalicylate, m.p. 48-50°C

(hexane),

methyl 3-allyl-5-methoxy-acetylsalicylate, m.p. (0.4 mm Hg) = 129-130°C and

methyl 3-allyl acetylsalicylate, m.p. (12 mm Hg) = 165-168°C.

(b) 6-methylchroman-8-carboxylic acid:

Dry hydrogen bromide gas (approx. 110 g) is bubbled in slowly

through a cooled (-5 - 0°C) and stirred mixture of methyl-3-allyl-5-methyl-acetylsalicylate (149 g) and benzoyl peroxide (3.5 g) in carbon tetrachloride (410 ml). Stirring is continued at -5 to 0°C

for a further 3 hours, after which the reaction mixture is allowed to stand at approx. 0°C overnight. The carbon tetrachloride and excess hydrogen bromide are driven off under vacuum. The residue (174 g) is dissolved in methanol (200 ml) and added to a solution of potassium hydroxide (18 g)

in methanol (250 ml) while maintaining the temperature at 25-30°C during the addition. Stirring is continued at this temperature for a further 30 minutes, after which the reaction mixture is refluxed for 1 hour and finally cooled to room temperature. Methanol is then distilled off in vacuo, and the residue is dissolved in water (400 ml), filtered and finally added to a mixture of hydrochloric acid (185 ml,

37%) and ice (300 g). The crystals are filtered off, washed with water and dried. The yield of impure acid is 105 g (91%), m.p. 118-121°C. Recrystallization from n-butyl acetate (315 ml) gives 81 g (77% recovery) of pure 6-methylchroman-8-carboxylic acid, m.p. 122-123°C.

The following chroman-8-carboxylic acids are prepared in the same way

manner:

6-chlorochroman-8-carboxylic acid, m.p. 159-160°C (xylene), 6-methoxychroman-8-carboxylic acid, m.p. 109-110°C

(isopropanol) and

chroman-8-carboxylic acid, m.p. 91-92°C (carbon tetrachloride). The compound homochromane-9-carboxylic acid (2,3,4,5-tetrahydro-1-benzoxepine-9-carboxylic acid) required above is prepared as follows: N,N,N',N'-tetramethylethylenediamine (25 ml) is added to a solution of n-butyllithium (0.13 mol) in hexane (240 mL) with stirring and cooling to maintain the temperature at 20 to 25°C.

A solution of homochromane (14.8 g, 0.1 mol, Ann. Chim. t. 3.

1968, 189) in hexane (50 mL) is added and the mixture is kept at 20 to 25°C for 5 hours. The resulting solution is then forced into a vessel in which hexane (200 mL) is stirred vigorously under carbon dioxide at slightly above atmospheric pressure. Water

(250 mL) is finally added to dissolve the lithium salt and the mixture is allowed to separate. The aqueous phase is drawn off and acidified at 0 to 10°C. The crystals are filtered off, washed with water and dried. The yield is 14.2 g (7 3%) of pure homochroman-9-carboxylic acid, m.p. 56-57°C, which cannot be separated from recrystallized material, m.p. 56-57°C (carbon tetrachloride-hexane).

Example 2

N-( 4-( 2-( 4- methoxy- 2- methyl- 2, 3- dihydrobenzo[ b] furan- 7- carboxamido)-ethyl)- benzenesulfonyl)- N'-( 4- methylcyclohexyl)- urea

4-(2-(4-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide (3.9 g) and anhydrous potassium carbonate (3.1 g) are stirred and boiled for 2 hours under reflux cooling in 50 ml of acetone. A solution of 1.7 g of 4-methylcyclohexyl isocyanate is then added, after which stirring and refluxing are continued for a further 16 hours. The reaction mixture is cooled, and a small amount of potassium carbonate is filtered off. Acetone is distilled off in vacuum from the filtrate, and the residue (4.9 g) is dissolved in water. The resulting solution is heated to 60°C for 1 hour and allowed to stand overnight. The pH is adjusted to 9.2, and the secreted N,N'-di-(4-methylcyclohexyl)urea is then filtered off, after which an excess of dilute hydrochloric acid is added. The crystals are suctioned off, washed with water and dried.

The yield of crude product with melting point 193-195°C is 3.5 g (66%).

Recrystallization from dimethylformamide-methanol gives pure N-(4-(2-(4-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1 ->(4-methylcyclohexyl)-urea with melting point 199-201°C.

The following sulfonylureas are prepared in the same way: N-(4-(2-(2-methylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(4-methylcyclohexyl)-urea, sm .p. 175-177°C (methanol-dimethylformamide) and

N-(4-(2-(6-methoxychroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N 1 -(4-methylcyclohexyl)-urea f , m.p. 159-161°C (methanol).

Example 3

N-( 4-( 2 - ( 2, 5- dimethyl- 2, 3- dihydrobenzo[b] furan- 7- carboxamido)- ethyl)-benzenesulfonyl)- N'- cycloheptylurea

Ethyl N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-carbamate (4.5 g) and cycloheptylamine (1, 25 g) is mixed in dimethylformamide (25 ml) containing 2 drops of triethylamine. The mixture is stirred at 75°C for 1 1/2 hours and then at 110°C for a further 1 1/2 hours, after which it is cooled to room temperature and poured into ice and water containing a small amount of dilute hydrochloric acid. The precipitate is filtered off, washed with water and dried. The yield of impure material is 4.6 g (90%). Recrystallization from dimethylformamide-water gives 2.9 g (63% recovery) of pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)- benzenesulfonyl)-N<1->cycloheptylurea,

sm.p. 208-210°C.

In the same way is obtained: N-(4-(2-(6-methylchroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N1-isobutylurea, m.p. 192-193°C (methanol),

N-(4-(2-(6-methylchroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclopentylurea f, m.p. 194-195°C (methanol),

N-(4-(2-(6-methylchroman-8-carboxamido)-ethyl)benzenesulfonyl)-N'-cyclohexylurea, m.p. 219-220°C (ethanol-dimethylformamide-water),

The following N-sulfonyl urea esters, which are used as starting materials above and in the following, are prepared by well-established methods from the alkali metal salts of the corresponding sulfonamides and ethyl chloroformate in dimethylformamide or acetone: Ethyl-N-(4-(2-(2,5 -dimethyl-2,3-dihydrobenzotb]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-carbamate, m.p. 199-201°C (dioxane-water),

ethyl N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-carbamate, m.p. 171-173°C (dioxane-water),

ethyl N-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfonyl)-carbamate, m.p. 178-181°C (dimethylformamide-water) and

ethyl N-(6-methylchroman-8-carboxamido)-ethyl)-benzenesulfonyl)-carbamate, m.p. 184-185°C (dioxane-water).

Example 4

N-( 4-( 2-( 2, 5- dimethyl- 2, 3- dihydrobenzo[b] furan- 7- carboxamido)- ethyl)-benzenesulfonyl)- N'-( 4- methoxycyclohexyl)- urea

1.82 g 4-methoxycyclohexylamine hydrochloride, 4.5 g ethyl-N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl )-carbamate, 1.32 g of triethylamine and 25 ml of dioxane are mixed and stirred at 75°C for 90 minutes. The temperature is then raised to 110°C, and stirring is continued for a further 90 minutes at 110°C. The reaction mixture is cooled and processed as in example 3. whereby 5.0 g (95%) of crude product is obtained. Recrystallization from methanol-water gives pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]-furan-7 -carboxamido)-ethyl)-benzenesulfonyl)-N'-(4-methoxycyclohexyl)-urea with melting point 166-168°C.

The following sulfonylureas are prepared by the same

method using dioxane or dimethylformamide as solvent: N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N1 - (2,5-endomethylene-cyclohexyl)-urea, m.p. 199-200°C (methanol-water),

N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(4-methoxycyclohexyl)-urea, sm .p. 170-172°C (methanol-water),

N-(4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N<1->(1,4-endoethylene-cyclohexyl)-urea, m.p. 175-176°C (methanol-water).

Example 5

N-( 4-( 2-( 6- chlorochroman- 8- carboxamido)- ethyl)- benzenesulfonyl)- N'-( trans- 4- methyl- cyclohexyl)- urea

A solution of 6-chlorochroman-8-carbonyl chloride (2.3 g,

sm.p. 96-97°C (methylene chloride-hexane), made from 6-chlorochroman-8-carboxylic acid and thionyl chloride) in acetone (30 ml) is added dropwise at 0 to 5°C to a stirred solution of N-(4-(2- aminoethyl)-benzenesulfonyl)-N<1->(trans-4-methylcyclohexyl)-urea (3.5 g)

in water (50 ml) and acetone (20 ml), while the pH value is kept at approx. 9.8 by simultaneous addition of 4N sodium hydroxide solution. Stirring is continued for a further 1 hour after the addition, and the pH value is then adjusted to approx. 2. The crystals are filtered off and washed, first with a mixture of acetone and water (1:1) and then

after with water. The yield of the impure material is 4.1 g (74%)

after drying at 60°C. Recrystallization from chloroform-methanol yields 2.8 g (68% recovery) of pure N-(4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N'-(trans-4-methylcyclohexyl )-urea, m.p. 190-191°C. The potassium salt of this compound is prepared by treatment with potassium hydroxide in aqueous acetone,

sm.p. 198-200°C.

Example 6

N-( 4-( 2-( 2, 5- dimethyl- 2, 3- dihydrobenzo[ b] furan- 7- carboxamido)- ethyl)-benzenesulfonyl)- N'- cyclohexylurea

0.7 g of N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(2-cyclohexenyl)-urea (melting point 176-177°C) is dissolved in 7 ml of dimethylformamide and hydrogenated at room temperature in the presence of 0.2 g of palladium on charcoal.

The calculated amount of hydrogen is consumed within a few minutes. The catalyst is filtered off after 35 minutes, and 21 ml of water is added. The separated crystals are suctioned off, washed with water and dried. 0.6 g of substance with a melting point of 203-206°C is recovered. Recrystallization from dimethylformamide-methanol yields 0.5 g of pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N '-cyclohexylurea with a melting point of 207-208°C.

In the same way: N-(4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzene-sulfonyl)-N 1 -cyclohexylurea, melting point 198-199°C, from N-(4 -(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N1 -

(2-cyclohexenyl)-urea (melting point 189-190°C).

Example 7

N-( 4-( 2-( 2, 5- dimethyl- 2, 3- dihydrobenzo[ b] furan- 7- carboxamido)-ethyl)- benzenesulfonyl)- N'-( 4- methyl- cyclohexyl)- urea

The sodium salt of 4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]-furan-7-carboxamido)-ethyl)-benzenesulfonamide (4.0 g) is mixed with potassium carbonate (1.4 g) and methyl N-(4-methyl-cyclohexyl)-carbamate (3.5 g, m.p. 64°C). The mixture is stirred at 130°C for 5 hours and then cooled. Acetone and dilute acid are added, and the precipitate is filtered off, treated with dilute ammonia containing some acetone, filtered and precipitated again by adding dilute acetic acid to the filtrate. The raw product is filtered off,

washed with water, dried and finally recrystallized from dimethylformamide-methanol to give pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)- benzenesulfonyl)-N'-(4-methyl-cyclohexyl)-urea, m.p. 183-185°C.

prepared in the same way: N-(4-(2-(2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(4-methyl-cyclohexyl)- urea,

sm.p. 159-160°C (methanol).

Example 8

_ N-( 4- ( 2- ( 2- methyl 1- 2, 3- dihydrobenzo[ b] furan- 7- carboxamido) - ethyl) -

benzenesulfonyl)- N'-cyclooctylurea

N,N-diphenylcarbamoyl chloride (3.6 g) is added to sodium

the salt of 4-(2-(2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide (5.7 g) in toluene (60 ml). The mixture is then refluxed for 3 hours and cooled. The solids are filtered off and suspended in dioxane. Cyclooctylamine (1.9 g) and glacial acetic acid (1 ml) are added, after which the mixture is refluxed for 2 hours. Dioxane is then removed by vacuum stripping, and the residue is treated with water and dilute acid. The impure material is filtered off and purified by treatment with dilute ammonia (1%) and acetone, followed by filtration and acidification of the filtrate with dilute hydrochloric acid. The crystals are filtered off,

washed with water, dried and finally recrystallized from dimethylformamide-methanol to give pure N-. (4-(2-(2-methyl-2, 3-dihydrobenzo [b]-furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N-cyclooctylurea,

sm.p. 175-176°C.

Example 9

N- ( 4- ( 2- ( 2- methyl- 2, 3- dihydrobenzo[ b] furan- 7- carboxamido)- ethyl) - benzenesulfonyl)- N'- cyclohexylurea

(a) The sodium salt of 4-(2-(2-methyl-2,3-dihydrobenzo[b]-furan-7-carboxamido)-ethyl)-benzenesulfonamide (7.6 g), cyclohexyl-

isothiocyanate (3 g) and potassium carbonate (6 g) are refluxed in acetone (100 ml) for 7 hours. The mixture is then cooled, and the solids are filtered off and washed with acetone. The wet cake is suspended in water (50 ml), and the mixture is acidified by adding acetic acid. The crystals are filtered off, washed with water, dried and finally recrystallized from methanol-water containing a small amount of acetic acid to give 8.0 g (80%) of N-(4-(2-(2-methyl-2,3- dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexyl-thiourea, m.p. 169°C, analysis: found 12.66% S (calcd 12.88% S). (b) A 30% solution of hydrogen peroxide (11 ml) is added dropwise at 40°C to a vigorously stirred suspension of N-(4-(2-(2-methyl-2,3-dihydrobenzo[b]furan-7- (carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexyl-thiourea (3 g) in 2N sodium hydroxide solution (50 ml). The mixture is then stirred for 30 minutes on a steam bath, after which it is cooled and acidified by adding dilute hydrochloric acid. The crystals are filtered off, washed with water and dried. The crude material is recrystallized from methanol-water containing a small amount of acetic acid to give 2.1 g (72%) of N-(4-(2-(2-methyl-2,3-dihydrobenzo[b]furan-7- carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, m.p. 171-175°C,

analysis: found 6.70% S (calculated 6.5.8% S) . Recrystallization from dimethylformamide-methanol gives pure material, m.p. 179-180°C.

Example 10

N-( 4-( 2-( 2, 5- dimethyl- 2, 3- dihydrobenzo[ b] furan- 7- carboxamido)-ethyl)- benzenesulfonyl)- N'-( 1, 4- endoethylene- cyclohexyl)- urea

A solution of 4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]-furan-7-carboxamido)-ethyl)-benzenesulfonamide (5.2 g) in dimethylformamide (20 ml) is slowly added to a suspension of sodium

hydride (0.4 g) in dimethylformamide (20 ml) at 40-60°C. Stirring is continued until the evolution of hydrogen ceases. The mixture is then cooled to 0°C and N,N<1->carbonyldiimidazole (2.8 g) is added. A solution of 1-aminobicyclo[2.2.2]octane-hydro-

bromide (3.5 g, m.p. 345°C) is added dropwise at 0 to 5°C

after which the reaction mixture is stirred at 85-95 C for 2 hours and finally cooled. Most of the dimethylformamide is driven off in vacuo, and the residue (14.8 g) is dissolved in 0.1 N sodium hydroxide solution (170 ml). A small amount of insoluble material is removed by filtration, and the filtrate is extracted with ether (3 x 50 ml) and

is then subjected to stripping in vacuum for a short time. The alkaline solution is then added to an excess of dilute hydrochloric acid,

and the precipitate is filtered off and washed carefully with water. The wet cake is redissolved in a mixture of 1% ammonia solution (30 ml) and acetone (15 ml). A small amount of insoluble material is removed by filtration, and the filtrate is added to an excess of dilute hydrochloric acid. The crystals are filtered off, washed with water and dried. The yield of impure material is 4.2 g (57%), m.p. 181-

183°C. Recrystallization from dimethylformamide-methanol gives 3.0 g (71% recovery) of pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]-furan-7-carboxamido)-ethyl- benzenesulfonyl)-N1 -(1,4-endoethylenecyclohexyl)-urea, m.p. 188-189° C. Analysis: found 63.96% C (calcd. 63.97%), 8.16% N (calcd. 8, 00%) and 6.15% S

(calculated 6.10%). The sodium salt of this compound is prepared by treatment with sodium hydroxide in aqueous acetone, m.p. 236-

238°C.

Example 11

N-( 4-( 2-( 2, 5- dimethyl- 2, 3- dihydrobenzo[ b] furan- 7- carboxamido)- ethyl)-benzenesulfonyl)- N'- cyclohexylurea

2.6 g of N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N^-cyclohexylurea methyl ether are dissolved in a few milliliters of glacial acetic acid and added to 2 5 ml of 20% hydrochloric acid. The mixture is stirred vigorously under reflux

cooling for 15 minutes, after which the formed suspension of crystals is cooled to room temperature. 50 ml of water is added, after which the crystals are suctioned off, washed with water and dried. The dividend of

crude product with melting point 202-205°C amounts to 1.8 g (71%). Recrystallization from dimethylformamide-methanol (3.6 ml + 9 ml) gives

1.3 g pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea with melting point 207-208 °C, corresponding to 72% being recovered during the purification.

The N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N1-cyclohexyl urea methyl ether used as starting material can be prepared as follows: A solution of 1.4 g of mercury(II) chloride in 20 ml of methanol is added to a solution of 0.6 g of sodium methylate in 50 ml of methanol.

2.6 g of N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo-[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexyl are then added -thiourea (melting point 159-160°C, prepared from the corresponding sulfonamide and cyclohexyl isothiocyanate and potassium carbonate in acetone as described in example 1), after which it is stirred under reflux for 2 hours. After cooling, the separated substance is filtered off, and the solution is evaporated in a vacuum. The resulting N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea methyl ether remains as a colorless, viscous oil , which solidifies into a low-melting glass (2.6 g). Thin-layer chromatography shows that there are only traces of impurities in the substance, which can therefore be used above without purification.

Example 12

N- ( 4- ( 2- ( 2, 5- dimethyl- 2, 3- dihydrobenzo[b] furan- 7- carboxamido)- ethyl) - benzenesulfonyl)- N'- cyclohexylurea

(a) 5 ml of 30% hydrogen peroxide solution is added dropwise while stirring to a 40°C warm solution of 0.53 g of N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzotb)furan-7-thiocarboxamido )-ethyl)-benzenesulfonyl)-N'-cyclohexylthiourea in a mixture of 10 ml of 2N sodium hydroxide and 5 ml of dioxane. After the addition is complete, stir for a further 5 minutes at 40°C and then for 30 minutes in a steam bath, after which it is cooled and an excess of diluted hydrochloric acid is added. The excreted substance is suctioned off, washed with water and dried. The crude product thus obtained dissolves clearly in methanol, after which it crystallizes spontaneously. The crystals are suctioned off, washed with methanol and dried. The yield of pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea with melting point 207-208°C amounts to 0.35 g (70%). (b) 0.53 g of N-(4-(2-(2,5-dimethyl--2,3-dihydrobenzo[b]furan-7-thiocarboxamido)-ethyl)-benzenesulfonyl)-N<1-> cyclohexylthiourea is stirred overnight at 60°C with a mixture of 1.7 g of mercury(II) chloride, 25 ml of water, 15 ml of 2N sodium hydroxide and 25 ml of dioxane. After cooling, the pH is adjusted to 9.2, and undissolved material is filtered off. The filtrate is made acidic, and the secreted substance is suctioned off, washed with water and dried. The yield of crude product with melting point 191-198°C amounts to 0.3 g (60%). Analysis: Calculated 6.42% S, found 6.12% S. By recrystallization from dioxane-water using activated carbon and then from dimethylformamide-methanol, pure N-(4-(2,(2,5-dimethyl-2,3-dihydrobenzo[b] furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea with melting point 207-208°C. (c) 0.52 g of N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-thiocarboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea is treated as described under b), whereby 0.3 g of crude product (60%) with melting point 192-197°C is obtained. Analysis: Calculated 6.42% S,

found 6.36% S. The substance can be purified in the manner indicated under b).

The starting materials used in the above, N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-thiocarboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylthiourea, melting point 183 -184°C (dimethylformamide-methanol), and N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzotb]furan-7-thiocarboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, melting point 170-171°C (dimethylformamide-methanol), can be prepared as described in example 1 from 4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-thiocarboxamido)-ethyl)- benzenesulfonamide, melting point 153-154°C when reacted with cyclohexyl isothiocyanate and cyclohexyl isocyanate respectively.

Example 13

N-( 4-( 2-( 2, 5- dimethyl- 2, 3- dihydrobenzo[ b] furan- 7- carboxamido)- ethyl)-benzenesulfonyl)- N'- cyclohexylurea

1.5 g N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylcarbodiimide (see below) dissolve in 30 ml of dioxane, after which 10 ml of water is added. The solution is stirred at room temperature for 2 hours (crystals separate after approx. 30 min.), after which the separated substance is brought into solution by adding 6N sodium hydroxide solution. The pH is adjusted to 9.2, and some undissolved matter is removed by filtration, after which the filtrate is added to an excess of dilute hydrochloric acid and ice. The substance first precipitates as an oil, but crystallizes on standing. The substance is suctioned off, washed with water and dried. The yield of crude product with melting point 198-203°C is 0.9 g (approx. 69%). Thin layer chromatography as well as IR spectroscopy suggest that the substance is almost pure. Recrystallization from dimethylformamide-methanol leads to pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylurea with melting point 207-208°C.

The N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)benzenesulfonyl)-N'-cyclohexylcarbodiimide used above as starting material can be prepared in the following way: 1.5 g N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylchloroformate amidine

(see below) is stirred in boiling chlorobenzene under reflux

cooling. Dry nitrogen is bubbled through the solution to

remove hydrogen chloride formed during the reaction. The development of hydrogen chloride ceases completely after approx. 3 hours, after which chlorine

benzene is distilled off in a vacuum. The remaining residue of 1.5 g still contains some chlorobenzene in addition to the desired N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzene- sulfonyl)-N'-cyclohexylcarbodiimide. The IR spectrum - 1 (1:3 in CCl4.)

shows a very strong absorption band at 2170 cm, which is characteristic of carbodiimides.

The intermediate product N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N1-cyclohexylchloroformic acid amidine used above can be prepared in the following way:

The phosgene is bubbled while stirring through a solution of

1.55 g N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylthiourea (melting point 159- 160°C) in 50 ml of dry tetrahydrofuran. The temperature thereby rises to 38°C within 20 minutes, after which it falls to 30°C within 2 hours. Excess phosgene and tetrahydrofuran are removed by careful distillation in a vacuum with a water bath (35°C) as a heat source. The remaining residue of 1.8 g still contains some solvent in addition to the desired N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzofb]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N <1->cyclohexylchloroformate amidine. A sample (0.3 g) of this residue is hydrolyzed in a mixture of 2N sodium hydroxide solution and dioxane under gentle heating for a few minutes. The pH is adjusted to 9.2, and a trace of undissolved material is removed by filtration. Addition of an excess of dilute hydrochloric acid precipitates a solid which is suctioned off, washed with water and dried. Recrystallization from dimethylformamide-methanol yields pure N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N1 - cyclohexylurea with melting point 207-208°C.

Example 14

N-( 4-( 2-( 6- chlorochroman- 8- carboxamido)- ethyl)- benzenesulfonyl)- N'- n-butylurea

1.16 g of n-butyl urea and 0.5 g of sodium hydride (50% dispersion in oil) are stirred and boiled for 2 hours under reflux cooling in 50 ml of dry benzene. It is then cooled to 60 C, and a solution of 4.16 g of 4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-

benzene sulphochloride in 25 ml of benzene and 10 ml of dioxane are added.

The mixture is stirred vigorously overnight at approx. 60°C, after which

it cools down to room temperature. The solid substance is sucked off and redissolved in water. The pH is adjusted to 9.2 and the solution

is filtered. The filtrate is acidified with an excess of dilute salt-

acid. The secreted substance is aspirated, redissolved in 40 ml of l%ig

ammonia water, filtered and reprecipitated with dilute hydrochloric acid.

After extraction and washing, the substance is dissolved in 4 ml of acetone and added

1 ml of 2N sodium hydroxide solution. The secreted sodium salt from

is soaked the next day and washed with a little dry acetone, after which the

dissolves in water. After adding an excess of acid, the secreted substance is sucked off, which is washed with water and dried. It thus

obtained crude product with melting point 172-176°C gives on recrystallization

lysis from methanol-dioxane-water the pure .N-(4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N<1->n-butylurea with melting point 180-181°C.

The 4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfochloride used above as starting material can be prepared

in the following way:

44.5 g of (2-(6-chlorochroman-8-carboxamido)-ethyl)-benzene

(prepared from 2-phenylethylamine and the acid chloride of 6-chlorochroman-8-

carboxylic acid by reaction in pyridine) is added in small portions to 164 g of chlorosulfonic acid at -20°C to -10°C. The temperature is then allowed to rise to room temperature and stirred for a further 30 minutes. at room-

temperature, after which the reaction mixture is poured into an excess of crushed ice with vigorous stirring. It is extracted with 2 x 400 ml of chloroform, the combined extracts are washed with water and dried over

magnesium sulfate. The chloroform is distilled off in a vacuum, and the residue is dissolved in 50 ml of acetone, after which a crystallization takes place

tion. The crystals are suctioned off, washed with acetone and then with

ether, after which they are air-dried. The yield of 4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfochloride is 26.5 g (45%), melting point 160-163°C. A sample of this substance gives when treated with

ammonia in dioxane 4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-

benzenesulfonamide, which is identical to the substance prepared in a different way (example 1).

Example 15

N-( 4-( 2-( 6- methylchroman- 8- carboxamido)- ethyl)- benzenesulfonyl)- N'-( 2- cyclohexenyl)- urea

A solution of 3.4 g of 4-(2-(6-methylchroman-8-carboxamido)-ethyl)-benzenesulfonamide in 45 ml of dimethylformamide is added dropwise with stirring to a slurry of 0.27 g of sodium hydride in 15 ml of dimethylformamide at 50 -60°C. The mixture is then heated to 100°C and stirred at this temperature until hydrogen evolution ceases. A solution of 2.0 g of phenyl N-(2;acyclohexenyl)-carbamate (melting point 113-115°C, prepared from 2-cyclohexenylamine and chloroformic acid phenyl ester in ether with triethylamine as acid binding agent) is then added in 25 ml of dimethylformamide, and the stirring at 100°C is continued for another 1 hour. Dimethylformamide is now distilled off under vacuum, and the residue is dissolved in a mixture of 250 ml of water, 2 ml of 4N sodium hydroxide solution and 100 ml of acetone. The pH is adjusted to 9.1, and a trace of undissolved material is removed by filtration. The filtrate is then dripped into a mixture of 15 ml of 4N hydrochloric acid, 50 ml of water and 100 g of crushed ice. The separated crystals are suctioned off, washed with water and dried. The yield of crude product with melting point 178-181°C is 4.0 g (88%). By recrystallization from acetone-water using activated carbon, pure N-(4-(2-(6-methylchroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N"-(2-cyclohexenyl)-urea with melting point 191-192°C.

In the same way: N-(4-(2-(6-chlorochroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N<1->(2-cyclohexenyl)-urea, melting point 189-190°C (methanol -dioxane-water),

N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(2-cyclohexenyl)-urea, m.p. 160-161°C (methanol-water),

N-(4-(2-(5-chloro-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(2-cyclohexenyl)-urea, m.p. 170-172°C (acetone-water), and

N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->(2-cyclohexenyl)-urea, m.p. 176-177<W>C (methanol-water).

Example 16

N-( 4-( 2-( 5- methyl- 2, 3- dihydrobenzo[b] furan- 7- carboxamido)- ethyl)-benzenesulfonyl)- N'- cyclohexylurea

10.8 g of 4-(2-(5-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, 9.2 g of anhydrous potassium carbonate and 4.5 g of cyclohexyl isocyanate are mixed with 2 50 ml anhydrous acetone and stir

under reflux overnight. After cooling, vacuum off

the secreted potassium salt, which is washed with acetone and then re-

dissolve in a mixture of 600 ml water and 200 ml acetone. pH in-

is set to 9.2 and some undissolved material is filtered out. The solution is dripped while stirring into a mixture of 25 ml of 4N hydrochloric acid and

200 ml of water. The separated crystals are suctioned off, washed with water and dried. The yield of crude product with melting point 202-204 c is 13.5 g (92%). Recrystallization from dimethylformamide (34 ml) and methanol (170 ml) gives 12.7 g of pure N-(4-(2-(5-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl) -benzenesulfonyl)-N<1->cyclohexylurea with a melting point of 203-204°C, corresponding to 94% being recovered by

the cleansing.

Prepared in a similar way: N-(4-(2-(5-methylbenzo[b]furan-7-carboxamido)-ethyl)-benzene-sulfonyl)-N1-cyclohexylurea f, melting point 201-202°C

(dimethylformamide-methanol),

N-(4-(2-(2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, melting point 183-184°C

(dimethylformamide-methanol), or melting point 157-158°C (precipitated in water),

N-(4-(2-(2,2,5-trimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylurea, melt-

point 170-171°C (dimethylformamide-methanol),

N-(4-(2-(2,3,5-trimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexyl urea,

melting point 210-211°C (dimethylformamide-methanol),

N-(4-(2-(6-chloro-2H-chromene-8-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, melting point 181-183°C

(dimethylformamide-methanol),

N-(4-(2-(5-chlorochroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, melting point 222-223°C (dimethylformamide-

methanol),

N-(4-(2-(6-bromochroman-8-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylurea, melting point 190-191°C (dimethylformamide-

methanol),

N-(4-(2-(5-bromo-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexyl urea,

melting point 177-178°C (dimethylformamide-methanol),

N-(4-(2-(5-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(trans-4-methyl-cyclohexyl)-urea, m.p. 159-160°C (dioxane-water),

N-(4-(2-(2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->(trans-4-methylcyclohexyl)-urea, melt-

point 201-202°C (dioxane-water),

N-(4-(2-(7-methylhomochroman-9-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, melting point 212-213°C (dimethylformamide-methanol),

N-(4-(2-(2,5-dimethylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, melting point 188-190°C (dimethylformamide-methanol),

N-(4-(2-(5-chloro-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea, melting point 154-155°C,

and

N-(4-(2-(5-bromo-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylurea, melting point 202-203°C.

The starting material used in example 16, 4-(2-(5-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 185-186°C (dimethylformamide-methanol), is prepared from 5-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid and 4-(2-aminoethyl)-benzenesulfonamide as described under example 1.

The following new sulfonamides are prepared in the same way

from the corresponding carboxylic acids: 4-(2-(2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 204-205°C (dioxane-water),

4-(2-(2,2,5-trimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 185-186°C (methanol),

4-( 2-(2,3,5-trimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 199-200°C (dimethylformamide-methanol),

4-(2-(5-methylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 163-164°C (dimethylformamide-methanol),

4-(2-(5-chlorochroman-8-carboxamido)-ethyl)-benzenesulfonamide, melting point 195-196°C (dimethylformamide-methanol),

4-(2-(6-bromochroman-8-carboxamido)-ethyl)-benzenesulfonamide, melting point 235-236°C (dimethylformamide-methanol),

4-(2-(5-bromo-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 252-253°C (dimethylformamide-methanol) ,

4-(2-(6-chloro-2H-chromene-8-carboxamido)-ethyl)-benzenesulfone-

amide, melting point 206-207°C - during decomposition - (dimethylformamide-

methanol),

4-(2-(7-methylhomochroman-9-carboxamido)-ethyl)-benzene-

sulfonamide, melting point 188-189°C (dimethylformamide-methanol),

4-(2-(2,5-dimethylbenzo[b]furan-7-carboxamido)-ethyl)-benzene-

sulfonamide, melting point 194-195°C (methanol),

4-(2-(5-chloro-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 224-226°C (dimethylformamide-methanol),

4-(2-(5-bromo-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 205-206°C (dimethylformamide-methanol),

4-(2-(5-Methoxybenzo[b]furan-7-carboxamido)-ethyl)-benzene-

sulfonamide, melting point 197-198°C (dimethylformamide-methanol),

4-(2-(5-Methoxy-2-methylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 206-207°C (dimethylformamide-methanol)

and

4-(2-(2,2-dimethyl-5-methoxy-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide, melting point 175-176°C (methanol).

The new carboxylic acids required for their production

above-mentioned sulfonamides, are produced in the following ways:

2,3-dihydrobenzo[b]furan-7-carboxylic acid, melting point 169--

170°C (glacial acetic acid) is produced in a 54% yield from 2,3-dihydro-

benzo [b] furan using n-butyllithium and carbon dioxide as

described for the homochromane-9-carboxylic acid under Example 1.

7-Methylhomochroman-9-carboxylic acid, melting point 91-92°C

(carbon tetrachloride-hexane) is prepared entirely analogously to homochroman-9-carboxylic acid (see example 1) from 7-methylhomochroman, which is prepared analogously to homochroman.

5-chlorochroman-8-carboxylic acid, melting point 161-163°C

(glacial vinegar), is prepared analogously with 6-methylchroman-8-carboxylic acid as described according to example 1, in that from methyl-3-allyl-4-

chlorosalicylate (example 1) first methyl 3-allyl-4-chloroacetylsalicylate is prepared, melting point 45-46°C (hexane).

6-bromochroman-8-carboxylic acid, melting point 167-168°C

(n-butyl acetate) is prepared analogously with 6-methylchroman-8-carboxyl-

acid via the following intermediates:

a) methyl 2-allyloxy-5-bromobenzoate,

boiling point (0.4 mm Hg) = 103-104°C,

melting point 31-32°C (hexane),

b) methyl 3-allyl-5-bromosalicylate,

boiling point (0.3 mm Hg) = 98-99°C, and

c) methyl 3-allyl-5-bromoacetylsalicylate,

melting point 66-67°C (hexane).

5-bromo-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid, melting point 208-209°C (glacial acetic acid) is prepared analogously to 2,5-dimethyl-2,3-dihydrobenzo[b]furan -7-carboxylic acid (according to example 1) from the intermediate products indicated immediately above under a) and b). The same applies to 2,3,5-trimethyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid, melting point 140-142°C (n-butyl acetate), as for this purpose it is prepared according to the methods specified under example 1 the following intermediates:

a) methyl 2-crotyloxy-5-methylbenzoate,

boiling point (0.25 mm Hg) = 97-98°C, and

b) methyl 2-a-methallyl-5-methyl salicylate,

boiling point (0.15 mm Hg) = 76-78°C.

2,2,5-trimethyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid is prepared as follows: 110 g methyl 3-3-methallyl-5-methyl salicylate and 125 ml 90% formic acid are stirred and boiled under reflux cooling for 2 hours. The formic acid is then distilled off in a vacuum and the residue (111 g) is mixed with a solution of 100 g of sodium hydroxide in 500 ml of water, after which it is stirred and boiled under reflux for 1 hour. The solution is then cooled, and an excess of hydrochloric acid is added. The crystals are sucked off and washed with water. After drying, the yield of the crude acid amounts to 96.4 g (93%). By recrystallization of n-butyl acetate, 80.8 g of pure 2,2,5-trimethyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid with a melting point of 169-17o°C are obtained.

Prepared in a similar way: 2,2-dimethyl-5-methoxy-2,3-dihydrobenzo[b]furan-7-carboxylic acid, melting point 141-142°C (n-butyl acetate).

The following new intermediates are required for the manufacture

of the two carboxylic acids above:

methyl 2-|3-methylyloxy-5-methylbenzoate, boiling point (0.2 mm Hg) = 108-110°C, and methyl 2-3-methylyloxy-5-methoxybenzoate, boiling point (1 mm Hg) = 128-129° C, which is prepared from methallyl chloride and respectively methyl 5-methylsalicylate and methyl 5-methoxysalicylate in dimethylformamide in the presence of anhydrous potassium carbonate and a little

sodium iodide, as the process is otherwise completely analogous to the other

corresponding processes described under example 1. In Claisen-

relocation is obtained accordingly:

methyl 3-3-methallyl-5-methyl salicylate, boiling point (0.2 mm Hg) =

96-97°C, and

methyl 3-3-methallyl-5-methoxysalicylate, boiling point (0.6 mm Hg) = 109-110°C.

5-Bromo-2,3-dihydrobenzo[b]furan-7-carboxylic acid, m.p

225-227°C (dioxane), and 5-chloro-2,3-dihydrobenzotb]furan-7-carboxyl-

acid, melting point 218-220°C (dioxane), produced by gla. eration or chlorination of 2,3-dihydrobenzo[b]furan-7-carboxylic acid in glacial acetic acid at 25-30°C in the presence of some iron.

5-Methoxy-2-methylbenzo[b]furan-7-carboxylic acid is prepared

in the following way:

a) methyl 2-3-chloroallyloxy-5-methoxybenzoate:

218 g of methyl 5-methoxysalicylate are placed under stirring

slowly to a slurry of 32 g of sodium hydride in 360 ml of dimethyl-

formamide at 60°C. It is stirred at this temperature until

hydrogen evolution ceases, after which it is heated to 95°C.

146 g of 2,3-dichloro-1-propene are now added at 95°C to 100°C over 30 min., and the mixture is then stirred at 100°C to 105°C for 3 hours. After cooling to room temperature, 20 ml of methanol is carefully added, and the solution is then poured into a mixture of 800 g of crushed ice, 600 ml of 5% sodium hydroxide solution and 1600 ml of toluene.

The water phase is separated and re-extracted with 400 ml of toluene. The

combined toluene solutions are washed with a saturated solution of

sodium chloride, after which the toluene is distilled off in a vacuum. The residue weighs 285 g, corresponding to approx. 92% yield, as it consists of -

almost pure methyl 2-3-chloroallyloxy-5-methoxybenzoate.

b) methyl 3-3-chloroallyl-5-methoxysalicylate:

Mix 285 g of 2-3-chloroallyloxy-5-methoxybenzoate with 285 ml

N-methyl-2-pyrrolidone and stirred under nitrogen at 200°C for 6 hours.

After cooling, the solution is poured into a mixture of 570 g of crushed ice,

17 ml of 37% hydrochloric acid, 228 g of sodium chloride, 630 ml of water and 570 ml of toluene. The water phase is separated and washed with 230 ml of toluene, after which toluene is distilled off from the combined toluene solutions in vacuum.

The residue (approx. 286 g) is dissolved in 140 ml of acetone, and it is added

first 14 g of activated carbon and 14 g of Hyflo and then slowly and while stirring a total of 1400 ml of isooctane. The coals are sucked off and isooctane

distilled from the filtrate in vacuo. Return is 262 g (92%)

almost pure methyl 3-3-chloroallyl-5-methoxysalicylate, which crystallizes on standing (the pure compound has a melting point of 46-47°C).

c) 5-Methoxy-2-methylbenzo[b]furan-7-carboxylic acid:

247 g of 3-3-chloroallyl-5-methoxysalicylate are placed in the course of

about. 10 minutes to a solution of 162 g of potassium hydroxide in 890 ml of 2-methoxyethanol. The mixture is stirred at approx. 116°C for 2 hours, after which it is cooled to 25°C. 1800 ml of water is then added, and the resulting solution is slowly added to a mixture of 290 ml of 37% hydrochloric acid and 1800 g of crushed ice. The crystals are sucked off and washed with water. After drying, the yield of the crude acid amounts to 173 g (87%), melting point 163-168°C. This substance is dissolved in a solution of 37 g of sodium hydroxide in 64 5 ml of water, after which it slowly

add 210 g of sodium chloride. The salted-out sodium salt is sucked off and washed with a saturated sodium chloride solution, after which the moist filter cake is redissolved in 2100 ml of water, and 17 g of activated carbon and 17 g of Hyflo are added. The coals are sucked off, and the colorless filtrate is added to a mixture of 130 ml of 37% hydrochloric acid and 1600 g of crushed ice. The crystals are suctioned off, washed with water and dried. Out-

the yield of pure 5-methoxy-2-methylbenzo[b]furan-7-carboxylic acid with melting point 171-172°C is 138 g, corresponding to 80% being recovered

during the cleansing.

In a similar way, the following is produced:

2,5-dimethylbenzo[b]furan-7-carboxylic acid, melting point 168-

169°C (n-butyl acetate),

5-chloro-2-methylbenzo[b]furan-7-carboxylic acid, melting point 237-238°C (n-butyl acetate), and

5-bromo-2-methylbenzo[b]furan-7-carboxylic acid, melting point 230-231°C (glacial vinegar), whereby the following new intermediates are prepared in a similar manner as above: methyl 2-3-chloroallyloxy-5-methylbenzoate , boiling point (0.2 mm Hg)= 119-120°C,

methyl 2-3-chloroallyloxy-5-chlorobenzoate, melting point 40-

41°C (n-hexane),

methyl 2-3-chloroallyloxy-5-bromobenzoate, melting point 51-52°C (n-hexane),

methyl 3-3-chloroallyl-5-methyl salicylate, boiling point (0.25 mm Hg) = 99-102°C,

methyl 3-3-chloroallyl-5-chlorosalicylate, used in the next

steps without purification,

methyl 3-3-chloroallyl-5-bromosalicylate, used in the next step without purification. The structure of the latter 2 compounds is easily confirmed by NMR spectroscopy, and the compounds are also almost pure when examined by thin-layer chromatography.

The 5-methylbenzo[b]furan-7-carboxylic acid is prepared as follows:

a) 7-bromo-5-methylbenzo[b]furan-2-carboxylic acid ethyl ester:

195 g of 3-bromo-2-hydroxy-5-methylbenzaldehyde, 215 g of diethyl bromomalonate and 186 g of anhydrous potassium carbonate are mixed with 600 ml of methyl isobutyl ketone and stirred at 100-110°C for 3 hours. After cooling to approx. At 50°C, most of the solvent is distilled off in a vacuum, and water is added. The separated crystals are suctioned off, washed with water and dried. The yield of crude product with melting point 78-80°C is 198 g (77.5%). By recrystallization from methanol, 168 g (85% recovered) of pure 7-bromo-5-methylbenzo[b]furan-2-carboxylic acid ethyl ester with a melting point of 83-84°C are obtained.

b) 7-bromo-5-methylbenzo[b]furan-2-carboxylic acid:

168 g of the pure ester prepared above are added to a

solution of 133 g of potassium hydroxide in a mixture of 1400 ml of water and 1400 ml of methanol. The mixture is stirred under reflux cooling for 30 min. A mixture of 225 ml of concentrated hydrochloric acid and 400 ml of water is then added, after which the resulting slurry is cooled to room temperature. The crystals are suctioned off, washed with water and dried. This gives 159 g (98.7%) of 7-bromo-5-methylbenzo[b]furan-2-carboxylic acid with a melting point of 269-271°C.

c) 7-bromo-5-methylbenzo[b]furan:

148 g 7-bromo-5-methylbenz6['b]furan-2-carboxylic acid, 4.8 g

copper powder and 770 ml of quinoline are stirred under nitrogen at 200-220°C for 30 minutes, after which it is cooled to room temperature. 800 ml of benzene is added, and the copper powder is filtered off. The benzene solution is extracted with 2N hydrochloric acid (3 x 1500 mL) to remove quinoline. The benzene is then distilled off, and the residue (122 g) is distilled in vacuum. This gives 118.2 g (97%) of 7-bromo-5-methylbenzo[b]furan, boiling point (10 mm) = 117-118°C.

d) 5-methylbenzo[b]furan-7-carboxylic acid:

118.2 g of 7-bromo-5-methylbenzo[b]furan are added dropwise while stirring

and cooling to 18 g magnesium shavings in 560 ml dry tetrahydrofuran,

as the temperature is kept below 30°C. After the addition of

is stirred for a further 15 min., after which the solution is forced into a container, in which 200 ml of dry tetrahydrofuran is stirred vigorously under a carbon dioxide atmosphere, the temperature below being kept at 10-15°C, and the carbon dioxide pressure being kept slightly above 1 atmosphere. After the reaction has ended, the carbon dioxide atmosphere is replaced with nitrogen, and a mixture of 62 ml of concentrated hydrochloric acid, 600 ml of water and 150 g of ice is added. Tetrahydrofuran is distilled off in a vacuum, and the secreted crude acid is sucked off and washed with water, after which it is redissolved in glacial acetic acid while heating to approx. 110°C. The solution is cooled, the crystals are sucked off, washed and dried.

The yield of 5-methylbenzo[b]furan-7-carboxylic acid with melting point 202-203°C is 78 g (79%).

In a similar way, the following is produced:

5-Methoxybenzo[b]furan-7-carboxylic acid, melting point 172-

173°C (glacial acetic acid), from 7-bromo-5-methoxybenzo[b]furan (Indian Acad. Sei. LVIII, 336 (1963) .

The 5-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid is prepared by hydrogenating the sodium salt of the 5-methylbenzo[b]furan-7-carboxylic acid in tetrahydrofuran-water (pH = 8) at a hydrogen

pressure of 4 atm. and a temperature of 40-50°C, using 5% palladium on coal as a catalyst. After addition of acid, an almost quantitative yield of pure 5-methyl-2,3-dihydrobenzo[b]furan-7-carboxylic acid with melting point 175-176°C can be isolated.

In a similar way, the following is produced:

5-Methoxy-2,3-dihydrobenzo[b]furan-7-carboxylic acid,

melting point 133-135°C.

Example 17

N-( 4-( 2-( 2, 2, 5- trimethyl- 2, 3- dihydrobenzo[ b] furan- 7- carboxamido)-ethyl)- benzenesulfonyl)- N'- cycloheptylurea

A solution of 3.9 g of 4-(2-(2,2,5-trimethyl-2,3-dihydro-benzotb]furan-7-carboxamido)-ethyl)-benzenesulfonamide in 45 ml of dimethylformamide is added dropwise with stirring to a suspension of 0.3 g of sodium hydride in 15 ml of dimethylformamide at 50°C. The mixture is then stirred at 100°C, until hydrogen evolution ceases, after which a solution of 3.1 g of 1-cycloheptyl-3,3-diphenylurea (melting point 145-146°C), prepared from diphenylcarbamoyl chloride and cycloheptylamine in dioxane with triethylamine as acid-binding agent) in 25 ml of dimethylformamide. It is stirred for a further 1 hour at 100°C, after which the dimethylformamide is distilled off in a vacuum. The residue is dissolved in a mixture of 2 ml of 4N sodium hydroxide, 250 ml of water and 300 ml of acetone. The resulting solution is extracted with 3 x 100 ml of ether to remove diphenylamine, after which the pH is adjusted to 9.1. A little undissolved substance is removed by filtration, after which the filtrate is dripped into a mixture of 15 ml of 4N hydrochloric acid and 100 ml of water. After stirring for some time, the secreted substance is sucked off, which is washed with water and dried. The yield of crude product with melting point 164-167°C is 4.1 g (77%). By recrystallization from methanol, 2.6 g of pure N-(4-(2-(2,2,5-trimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N' are obtained -cycloheptylurea with a melting point of 171-172°C, corresponding to 61% being recovered during the purification.

Example 18

N-(4-(2-(2,5-Dimethylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(trans-4-methylcyclohexyl)-urea

3.7 g of 4-(2-(2,5-dimethylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonamide and 1.8 g of trans-4-methylcyclohexyl isocyanate as well as 3.2 g of anhydrous potassium carbonate are stirred overnight under reflux in 100 ml of acetone. The mixture is then worked up as described in example 2, whereby 4.4 g (85%) of crude product with a melting point of 194-196°C is obtained. By recrystallization from 44 ml of water and 44 ml of dioxane, 3.6 g of pure N-(4-(2-(2,5-dimethylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-( trans-4-methylcyclohexyl)-urea with a melting point of 198-199°C, corresponding to 81% being recovered during the purification.

In the same way: - N-(4-(2-(5-methylbenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N1-(trans-4-methylcyclohexyl)-urea, melting point 174 -175°C (dioxane-water).

Example 19

The sodium salt of N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea

50 g of N-(4-(2-(2,5-dimethyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexyl urea are dissolved at room temperature in a solution of 2.4 2 g of sodium in 350 ml of methanol. 1750 ml of ether is added, after which the separated crystals are suctioned off and washed with ether. After drying phase 49 g (94%) off

the sodium salt with a melting point of 244-245°C.

In the same way is prepared: N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-(trans-4 -methyl-cyclohexyl)-urea sodium salt, melting point 261-262°C,

N-(4-(2-(2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N'-cyclohexylurea sodium salt, mp 237-238°C, and

N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylurea sodium salt, melting point 249-251 °C.

Example 20

The potassium salt of N- ( 4- ( 2- ( 2, 3- dihydrobenzo[b] furan- 7- carboxamido)-ethyl)- benzenesulfonyl)- N'- cyclohexylurea

4.7 g of N-(4-(2-(2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexylurea are added with stirring to a solution of 0.59 g of potassium hydroxide in 15 ml of methanol. A clear solution is first formed, after which the potassium salt begins to crystallize. 7 5 ml of diethyl ether are added slowly,

after which the crystals are suctioned off and washed with diethyl ether. The yield of the potassium salt is 4.4 g (86.5%), melting point 247-249°C.

In the same way: N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N1-(trans-4- methylcyclohexyl)-urea potassium salt, melting point 170-172°c, and

N-(4-(2-(5-methoxy-2-methyl-2,3-dihydrobenzo[b]furan-7-carboxamido)-ethyl)-benzenesulfonyl)-N<1->cyclohexyl-urea potassium salt, melting point 232 -233°C.

Claims (1)

Analogous method for the production of blood sugar- lowering benzenesulfonylurea derivatives of the general formula where R<1> means n-butyl, isobutyl, cyclohexenyl, cycloalkyl with 5-8 ring carbon atoms, 2,5-endomethylene-cyclohexyl, endoethylene- cyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl or 4-methoxycyclohexyl, R<2> means hydrogen, or methyl, methoxy, bromine or chlorine in the p- or preferably in the m-position to the CONH group of the benzene ring, R 3 and R 4 may be the same or different and mean hydrogen or methyl, and A means the chain of 2-4 carbon atoms that completes a benzfuran, dihydropbenzofuran, chromane, 2H-chromene or homochroman ring system, or salts thereof with bases, characterized by (a) that a p-acylamidoethylbenzenesulfonamide with the formula: where A, R 2 , R 3 and R 4 have the meanings given above, or a salt thereof, is reacted with a compound of the formula R"^-Z, where R<1> has the meaning given above, and where Z means one isocyanate residue, a carbamic acid ester residue, a thiol carbamic acid ester residue, a carbamide halide residue, a hydrocarbon substituted or an unsubstituted urea residue, an acylurea residue or a nitrourea residue, or by reacting a salt of the above sulfonamide with an amine of the formula R^NH.,, where R"*" has the above meaning, in the presence of N,N'-carbonyldiimidazole, or (b) that a compound of the formula: where A, R2, R3 and R<4> have the meanings given above, and X1 means an isocyanate residue, a carbamide ester residue, a carbamide halide residue, a thiolcarbamide ester residue, a hydrocarbon substituted or unsubstituted urea residue, an acylurea residue, a semicarbazide residue, a semicarbazone residue or imino-1 ,3-oxathiolane, is reacted with an amine R NH^ where R"*" has the above meaning, or a salt thereof, or (c) that the group 2 3 4 where A, R . R and R have the meanings given above, are introduced in one or more steps by acylation of a p-aminoalkyl-benzene-sulfonylurea with the formula where R" has the above meaning, or (d) that in the presence of a catalyst, a benzenesulfonylurea with the formula is hydrogenated where R° means an unsaturated group, which in the process is converted into a saturated R^ group, including in particular cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 2,5-endomethylenecyclohexyl or endoethylenecyclohexyl, and A, R <2>, 3 4 R and R have the meanings given above, or (e) that one hydrolyzes a compound with the formula: or or 12 3 4 where A, R , R , R and R have the meanings given above and T means halogen,' preferably chlorine, the remaining part of an isourea ether or the remaining part of an isothiourea ether, or (f) that, in particular by treatment with oxidizing agents or by treatment with oxides or salts of metal, exchanges sulfur with oxygen in a compound of the formula or or 12 3 4 where A, R , R , R and R have the meanings given above, or (g) that one adds water to a benzenesulfonyl carbodiimide with the formula 12 3 4 where A, R , R , R and R have the meanings given above, or (h) that one reacts a p-acylamidoalkylbenzenesulfonyl halide with the formula 3 4 21 where A, R and R have the meanings given above, R means chlorine, bromine or methyl, and X 3 means halogen, preferably chlorine, with an alkali metal salt of a urea of the formula H^NCONH-R 1 , where R has the above meanings, after which the thus produced benzenesulfonylureas are optionally converted into physiologically acceptable salts, preferably alkali metal salts, by treatment with bases.