US3712905A - P-carbamoylethylphenylsulfonyl derivatives - Google Patents

Abstract

COMPOUNDS OF THE CLASS OF 1-(P-CARBAMOYLETHYLPHENYLSULFONYL)-2-IMINO-IMIDAZOLIDINES AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF HAVE HYPOGLYCEMIC ACTIVITY; THE COMPOUNDS ARE ACTIVE INGREDIENTS OF PHARMACEUTICAL COMPOSITIONS AND CAN BE USED FOR THE TREATMENT OF DIABETES; AND ILLUSTRATIVE EMBODIMENT IS 1(P-(2 - (PROPYLCARBAMOYL) - ETHYL) - PHENYLSULFONYL)-2IMINO-3-SEC. BUTYL-IMIDAZOLIDINE.

Description

United States Patent U.S. Cl. 260309.7 3 Claims ABSTRACT OF THE DISCLOSURE Compounds of the class of l-[p-carbamoylethylphenylsulfonyl]-2-imino-imidazolidines and the pharmaceutically acceptable acid addition salts thereof have hypoglycemic activity; the compounds are active ingredients of pharmaceutical compositions and can be used for the treatment of diabetes; and illustrative embodiment is l- [p-[Z (propylcarbamoyl) ethyl] phenylsulfonyl]-2- imino-3-sec.butyl-imidazolidine.

The present invention relates to derivatives of l-[pcarbamoylethyhphenylsulfonyl1-2-imino imidazolidines, to pharmaceutical compositions containing these compounds and to the use thereof.

More particularly, the present invention relates to compounds of formula R is alkyl having at most six carbon atoms, cycloalkyl having from five to nine carbon atoms, allyl or benzyl;

R is hydrogen, methyl or ethyl;

R is hydrogen or alkyl having at most four carbon atoms;

R, is hydrogen or methyl; or

R and R together are pentamethylene;

and the pharmaceutically acceptable acid addition salts thereof.

These compounds have been found to have a hypoglycemic effect in warm-blooded animals upon oral or parenteral administration. This activity, in combination with a favourable therapeutic index, characterizes the compounds of the present invention as being suitable for the treatment of diabetes mellitus.

The hypoglycemic action can be demonstrated in standard tests on experimental animals.

In the compounds of Formula 1, R as alkyl, can be the methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tertbutyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, l-methylbutyl, l-ethylpropyl, 1,2-dimethylpropyl, 1,2-dimethylbutyl or the hexyl group; as cycloalkyl, R can be the cyclopentyl, 2- and 4-methylcyclohexyl, cyclohcxyl,

3,712,905 Patented Jan. 23, 1973 cycloheptyl, cyclooctyl or trimethylcyclohexyl group, such as, e.g. the 3,3,S-trimethylcyclohexyl group.

The substituent R as the alkyl group, can be anyone of the alkyl groups listed under R having at most 4 carbon atoms.

Using the process according to the invention, compounds of Formula I are produced by reacting a reactive functional derivative of a sulfonic acid of formula wherein R and R have the meaning given under Formula I, with a compound of formula wherein R and R have the meaning given under Formula I; and optionally, converting the reaction product with an inorganic or organic acid into an addition salt.

A suitable functional derivative of a sulfonic acid of Formula II is, e.g. halide, especially a chloride, or also an anhydride of formula The reaction is performed preferably in the presence of an inert organic solvent which is miscible or nonmiscible with Water, in the presence or absence of water. Suitable inert organic solvents, for example, are hydrocarbons such as benzene, toluene or xylene, ethereal liquids such as ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, and lower ketones such as acetone or methyl ethyl ketone. It is advantageous to add an acid-binding agent to the reaction solution. Suitable acid-binding agents are, e.g. inorganic bases or salts, e.g. alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates or alkali metal phosphates, such as the corresponding sodium or potassium compounds. It is also possible to use organic bases such as, e.g. pyridine, trimethylamine or triethylamine, N,N-diisopropylethylamine or collidine, which, added in excess, may also be used as solvent.

Starting materials of Formula II are, e.g. such compounds of which the substituents R and R have the meaning as listed under Formula I. Such starting materials, snlfonyl chlorides, can be produced, e.g. by reacting hydrocinnarnic acid amides with chlorosulfonic acid.

Hydrocinnamic acid amides are produced, e.g. by starting with hydrocinnamic acid chloride which can be produced, according to Mohr, Journal fiir praktische Chemie (Journal for practical Chemistry) [2] 71, 322 (1905), from hydrocinnamic acid and thionyl chloride. From hydrocinnamic acid chloride and methylamine in the presence of potassium hydroxide solution is obtained, according to Taverne, Rec. trav. chim. Pay-Bas 16, 39 (1897), hydrocinnamic acid methylamide. Other hydrocinnamic acid amides used according to the invention are produced analogously using corresponding amines.

The salts of compounds of Formula I, are produced, e.g. by reaction of these compounds with the equivalent amount of an acid in a suitable aqueous-organic or organic solvent such as, e.g. methanol, ethanol, diethyl ether, chloroform or methylene chloride.

For application as medicaments it is possible to use, instead of the free compounds of Formula I, pharmaceutically acceptable salts thereof with acids. Suitable addition salts are, e.g. salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, fi-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, salicylic acid, phenylacetic acid, mandelic acid andembonic acid; as well as salts with hypoglycemic sulfonyl ureas, such as, e.g. p-toluenesulfonylbutyl urea, pchlorobenzenesulfonylpropyl urea, p-[2-(2 methoxy-S- chlorobenzamido)-ethyl]-phenylsulfonylcyclohexyl urea.

For their intended use, the compounds of the invention are administered in amounts depending on the species, the age, weight and the particular condition of the individuals being treated, and the mode of administration. In general, the daily dosage varies between about 0.1 and 100 mg./kg. of body weight for warm-blooded animals. Suitable dosage units such as drages or tablets, contain preferably 10-500 mg. of an active substance according to the invention, i.e. 20 to 80% of a compound of 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, to form tablets or drage cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide; or they are coated with a lacquer dissolved in readily volatile organic solvents or solvent mixtures. Dyestuffs may be added to these coatings, e.g. for identification of the various dosage amounts.

Further suitable dosage units for oral administration are hard gelatin capsules, as Well as soft closed capsules made from gelatine and a softener, such as glycerin. The hard capsules contain the active substance preferably as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate, and optionally stabilisers such as sodium metabisulphite (Na S O or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby likewise stablisers can be added.

The following prescriptions serve to further illustrate the preparation of tablets and drages.

(a) An amount of 1000 g. of 1 [p-[2 (propylcarbam0yl)-ethyl]-phenylsulphonyl] 2 imino 3 cyclohexyl-imidazolidine is mixed with 500 g. of lactose and 270 g. of potato starch; the mixture is moistened with an aqueous solution of 8.0 g. of gelatine, and then granulated through a sieve. After drying of the granulate, 60.0 g. of potato starch, 60.0 g. of talcum, 10.0 g. of magnesium stearate and 20.0 g. of colloidal silicon dioxide are mixed in; the mixture is subsequently pressed to form 10,000 tablets each weighing 200 mg. and each containing 100 mg. of active substance. Optionally, the tablets can be provided with grooves to facilitate a more precise adjustment of the dosage amount.

(b) A granulate is produced from 1000 g. of 1 [p- [2 (propylcarbarnoyl)-ethyl]-phenylsulphonyl]-2-imino- 3-cyclohexyl-imidazolidine, 345.0 g. of lactose, and the aqueous solution of 6.0 g. of gelatine; the granulate is then mixed, after being dried, with 10.0 g. of colloidal silicon dioxide, 40.0 g. of talcum, 40.0 g. of potato starch and 5.0 g. of magnesium stearate; and this mixture is then pressed to form 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 533.0 g. of crystallizsed saccharose, 20.0 g. of shellac, 75.0 g. of gum arabic, 250 g. of talcum, 20 g. of colloidal silicon dioxide and 1.5 g. of dyestuff; and then dried. The obtained drages each weight 240 mg. and each contain mg. of active substance.

The following examples further illustrate production of the new compounds of Formula I, and of intermediate products not described hitherto; the examples, howevver, in no way constitute the only embodiments thereof. The temperatures are given in degrees centigrade.

EXAMPLE I (a) An amount of 17.7 g. 1-sec.buty1-2-imino-imidazolidine hydrochloride is dissolved in 100 ml. of water; to this solution is then added a solution of 29.0 g. of N- propyl-p-chlorosulphonyl-hydrocinnarnide in ml. of acetone. To the obtained solution is added dropwise a solution of 8 g. of sodium hydroxide in 35 ml. of water, thereby the temperature is not to exceed 35. After this dropwise addition, stirring proceeds for a further 15 minutes at room temperature, after which the solution is refluxed for 2 hours. The acetone is evaporated off in vacuo, and the precipitated oil extracted with methylene chloride. The organic phase is separated, washed with water, dried with sodium sulphate, and concentrated by evaporation. The residue is recrystallised from ethyl acetate, and l-[p- [2 (propylcarbamoyl)-ethyl]-phenylsulphonyl]-2 irnino- 3-sec.butyl-imidazolidine is obtained, which melts at 111- 1 13 The following are obtained in an analogous manner:

From 19.0 g. of 1-cyclopentyl-Z-imino-imidazolidine hydrochloride and 29.0 g. of N-n-propyl-p-chlorosulphonyl-hydrocinnamamide is obtained:

1 [p-[2 (n-propylcarbamoyl)-ethyl]phenylsulphony1]- 2-imino-3-cyclopentyl-imidazolidine, M.P. 144146 from ethyl acetate;

From 20.4 g. of 1-cyclohexyl-2-imino-imidazolidine hydrochloride and 29.0 g. of N-n-propyl-p-chlorosulphonyl-hydrocinnamamide is obtained:

1 [p-[2 (n-propylcarbamoyl)-ethyl]phenylsulphonyl]- 2 imino-3-cyclohexyl-imidazolidine, M.P. 147149' from ethyl acetate;

From 21.8 g. of 1-cycloheptyl-2-imino-imidazoline hydrochloride and 29.0 g. of N-n-propyl-p-chlorosulphonyl-hydrocinnamamide is obtained:

1 [p-[2 (n-propylcarbamoyl)-ethyl]phenylsulphonyl]- 2-imino-3-cycloheptyl-imidazolidine, M.P. 144-146 from ethyl acetate;

From 17.8 of 1 isobu-tyl 2 imino-imidizolidine hydrochloride and 29.0 g. of N-n-propyl-p-chlorosulphonylhydrocinnamamide is obtained:

1 [p- [2 (n-propylcarbamoyl)-ethyl]phenylsulphonyl]- 2-imino-3-isobutyl-imidazolidine, M.P. 108111 from ethyl acetate/cyclohexane;

From 21.8 g. of 1-(4-methylcyclohexyl)-2-imino-imidazolidine hydrochloride and 26.2 g. of N-methyl-p-chlorosulphonyl-hydrocinnamamide is obtained.

1 [p-[2 (n-butylcarbamoyl)-ethyl]-phenylsulphonyl]- 2 imino 3-(4-methylcyclohexyl)-imidazolidine, M.P. 167168.5 from ethyl acetate;

From 24.6 g. of 1-(3,3,5-trimethylcyclohexyl)-2-iminoimidazolidine hydrochloride and 26.2 g. of N-methyl-pchlorosulphonyl-hydrocinnamamide is obtained:

1 [p-[2 (n-propylcarbamoyl)-ethyl]phenylsulphonyl]- 2 imino-3-(3,3,5 trimethylcyclohexyl)-imidazo1idine, M.P. 147-148 from ethyl acetate;

From 26.8 g. of 1-(p-isopropyl-1-phenylethyl)-2-iminoimidazolidine hydrochloride and 26.2 g. of N-methyl-pchlorosulphonyl-hydrocinnamamide is obtained:

1 [p- [2 (n-propylcarbamoyl)-ethyl]phenylsulphonyl] 2 imino 3 (p-isopropyl-wmethylbenzyl)-imidazhdine, M.P. 151-152 from ethyl acetate;

From 21.8 g. of 1-(4-methylcyclohexyl)-2-imino-imidazolidine hydrochloride and 30.4 g. of N-isobutyl-pchlorosulphonyl-hydrocinnamamide is obtained:

1 [p-[2 (n-propylcarbarnoyl) -ethyl]phenylsulphonyl]- 2-imino 3 (4-methylcyclohexyl)-imidazolidine, M.P. 158-159 from ethyl acetate;

From 20.6 g. of 1-(1,Z-dimethyl)-2-imino-imidazolidine hydrochloride and 30.4 g. of N-isobutyl-p-chlorosulphonyl-hydrocinnamamide is obtained:

1 [p-[2 (n-propylcarbamoyl)-ethyl]phenylsu1phonyl]- 2 imino-3-(1,2 dimethylbutyl)-imidazolidine, M.P. 118-122 from ethyl acetate;

From 17.8 g. of 1-isobutyl-2-imino-imidazo1idine hydrochloride and 30.4 g. of N-isobutyl-p-chlorosulphonylhydrocinnamamide is obtained:

1 [p-[2 (n-isobutylcarbamoyl)ethyl] phenylsulphonyH- 2-imino-3-isobutyl-imidazolidine, MJP. 131-133 from methyl ethyl ketone;

From 24.6 g. of 1 {3,3,5 trimethycyclohexyll-Z- imino-imidazolidine hydrochloride and 30.4 g. of lfI-rsobutyl-p-chloroosulphonyl-hydrocinnamamide is obtained:

1 [p-[Z (n-propylcarbamoyl)-ethyl]phenylsulphonyl]- 2-imino 3 (3,3,5-trimethylcyclohexyl)-im1dazol1d1ne, M.P. 151-153 from ethyl acetate;

From 19.0 g. of 1-cyclopentyl-2-imino-imidazolidine hydrochloride and 30.4 g. of N-n-butyl-p-chlorosulphonylhydrocinnamamide is obtained:

1 [p-[Z (n-butylcarbamoyl)-ethyl]-phenylsulphonyl]- 2-imino 3 cyclopentyl-imidazolidine, M.P. 139-141 from ethyl acetate;

From 20.6 g. of 1-(1,2-dimethylbutyl)-2-imino-imidazolidine hydrochloride and 30.4 g. of N-n-butyl-p-chloro sulphonyl-hydrocinnamamide is obtained:

1 [p [2 butylcarbamoyl) ethyl]-phenylsu lphonyl]- Z-imino 3 (1,2-dimethylbutyl)-imidazo1id1ne, M.P. 123-125 from ethyl acetate;

From 20.4 g. of 1-cyclohexyl-2-imino-imidazo1idine hydrochloride and 30.4 g. of N-n-butyl-p-chlorosulphonylhydrocinnamamide is obtained:

1 [p-[Z (butylcarbamoyl)-ethy1]-phenylsulphonyl]- 2-imino 3 cyclohexyl-imidazolidine, M.P. 161-163 from acetone;

From 21.8 g. of 1-(2-rnethylcyclohexyl)-2-imino-imidazolidine hydrochloride and 30.4 g. of N-n-butyl-pchlorosulphonyl-hydrocinnamamide is obtained:

sulphonyl-hydrocinnamamide is obtained: 1- [p-[2-(ethylcarbamoyl)-ethyl] phenylsulphonyl] 2 imino-3-(2- methylcyclohexyl)-imidazolidine, M.P. 165-167 from acetone;

From 13.8 g. of 1-methyl-2-imino-imidazolidine hydrochloride and 27.6 g. of N-ethyl-p-chlorosulphonyl-hydrocinnamamide is obtained: l-[p-[2-(ethylcarbamoyl)ethyl] phenylsulphonyl] 2- imino-3-methyl-imidazolidine, M.P. -97 from ethyl acetate.

(b) The N-propyl-p-chlorosulphonyl hydrocinnamamide used as staring product is produced in the following manner:

An amount of 19.1 g. of N-propyl-hydrocinnamamide, M.P. 52-54", is added in portions, with stirring, to 35 ml. of chlorosulphonic acid. The mixture is afterwards stirred for 3 hours at 60, whereupon it is poured on to ice. The precipitated product is extracted with chloroform. The organic phase is washed with water, dried with sodium sulphate, filtered, and concentrated by evaporation. The residue, N-propyl'p-chlorosulphonyl-hydrocinnamamide, is further used, as oil, in the crude condition.

The following are obtained in an analogous manner:

From 16.3 g. of N-methyl-hydrocinnamamide, M.P. 59-60", is obtained: N-methyl-p-chlorosulphonyl-hydrocinnamamide, M.P. 219-221 from acetone/water;

From 20.5 g. of N-isobutyl-hydrocinnamamide, M.P. 58-61- is obtained: N-isobutyl-p-ch1orosulphonyl-hydrocinnamamide, which is further used, as oil, in the crude state;

From 20.5 g. of N-n-butyl-hydrocinnamamide, M.P. 25, is obtained: N-n-butyl-p-chlorosulphonyl-hydrocinnamamide, which is further used, as oil, in the crude state;

From 17.7 g. of N-ethyl-hydrocinnamamide, M.P. 58-60, is obtained: N-ethyl-p-chlorosulphonyl-hydrocinnamamide, which is further used, as oil, in the crude state.

EXAMPLE 2 Analogously to Example 1(a) are obtained:

From 20.6 g. 1-n-butyl-2-imino-S-ethyl-imidazolidinehydrochloride and 31.8 g. N-n-butyl-N-methyl-p-chlorosulfonyl-hydrocinnamamide, 1-[p-[2-(N-n-methyl carbamoyl)ethyl]-phenylsu1fonyl] 2 imino-3-n-butyl-4- ethyl-imidazolidine as an oil.

From 21.8 g. l-cyclohexyl-Z-imino-S-methyl-imidazolidine-hydrochloride and 31.8 g. N-nbutyl-N-methyl-pchlorsulfonyl-hydrocinnamamide, il-[p-[Z-(N-n-butyl N- methyl-carbamoyl)-ethyl]-phenylsulfonyl]-2-imino 3-nbutyl-4-imidazolidine as an oil.

From 16.2 1-allyl-2-imino-imidazolidine-hydrochloride and 31.6 g. N,N-pentamethylene-p-chlorsulfonyl-hydrocinnamamide, 1-[p-[2-(N,N-pentamethylene carbamoyl)-ethyl]-phenylsulfonyl]-2-imino-3-allyl imidazolidine M.P. 89-91.

From 21.2 g. 1-benzyl-2-imino-imidazolidine-hydrochloride and 31.6 g. N,N-pentamethylene-p-chlorosulfonyl-hydrocinnamamide, 1- [p- [2-(N,N-pentamethylenecarbamoyl)-ethyl]-phenyl-sulfonyl.] 2 imino-3-benzylimidazolidine M.P. 88-90.

From 20.4 g. 1-cyclohexyl-2-imino-imidazolidine-hydrochloride and 31.6 g. N,N-pentamethylene-p-chlorsulfonyl-hydrocinnamamide, l-[p-[2-(N,N-pentamethylenecarbamoyD-ethyl]-phenylsulfonyl]-2 imino 3 cyclohexyl-imidazolidine M.P. 108-110".

From 21.8 g. l-cyclohexyl-2-imino-S-methyl-imidazolidine-hydrochloride and 31.6 g. N,N-pentamethylene-p chlorosulfonyl-hydrocinnamamide l-[p-[2-(N,N pentamethylene-carbamoyl)-ethyl]-phenylsu1fonyl] 2 imino- 3-cyclohexyl-4-methyl-imidabolidine, M.P. 109-110.

The N-substituted chlorosulfonyl-hydrocinnamamides used as starting materials can be obtained analogously to Example 1(b).

7 What is claimed is: 1. A compound of formula or the pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1, which is 1-[p-[2- (propylcarbamoyl)-ethyl]-phenylsulfonyl] 2 imino-3- sec.butyl-imidazolidine.

3. A compound according to claim 1, which is, 1-[p-[2- (n-butylcarbamoyl)-ethyl]-phenylsulfonyl] 2 imino-3- cyclopentyl-imidazolidine.

References Cited UNITED STATES PATENTS 3,538,085 11/1970 Dietrich 260309.7

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

260293.7, 543 R, 544 M, 545 R, 558 R; 424267, 273