US3725430A - DERIVATIVES OF p-AMINOALKYL BENZENESULFONAMIDES - Google Patents

DERIVATIVES OF p-AMINOALKYL BENZENESULFONAMIDES Download PDF

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US3725430A
US3725430A US00061510A US3725430DA US3725430A US 3725430 A US3725430 A US 3725430A US 00061510 A US00061510 A US 00061510A US 3725430D A US3725430D A US 3725430DA US 3725430 A US3725430 A US 3725430A
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imino
phenylsulphonyl
imidazolidine
ethyl
aminoethyl
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H Dietrich
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/46—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms attached to said nitrogen atoms

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  • the present invention relates to new derivatives ofpaminoalkyl benzenesulfonamides, processes for their preparation, to medicaments containing'the new compounds and their use.
  • the present invention concerns compounds of the formula I,
  • R is alkyl having oneito six carbon atoms, allyl, cycloalkyl having five to eight carbon atoms, or cycloalkenyl having five to eight carbon atoms;
  • R is hydrogen, ethyl or methyl;
  • R can denote cyclopentyl, which can be optionally substituted by alkyl having one-three carbon atoms; cyclohexyl, which can besubstituted by ethyl or methyl; cycloheptyl, optionally substituted by methyl; as well ascyclooctyl; as cycloalkenyl, R, can denote-2-cyclopenten-l yl, 2-cyclohexen-lyl, 3-cyclohexen l yl, 2-methyl-2-cyclohexen l-yl, 3--
  • the substituent R embraces the'same alkyl, cycloal-- kyl or cycloalkenyl group'skas stated'under' R asalkenyl, R can denoteallyLfl -methylallyl,2-methylallyl,2 or 3-butenyl, or 2-, '3- or 4-pentenyl.
  • Suitable as reactive derivatives of a carbarnic acid or thioca'rbamic acid of formula III are, e.g. the halides,
  • the chlorides especially the lower alkyl esters, particularly'the methyl or ethyl esters, the phenyl esters, the amides, the lower monoor dialkylamides, in particular the N-methyl amides and the N,N-dirnethylamides, the diphenylamides, also the N-acylamides such as, e.g. the
  • the reaction is performed, e.g. at room temperature, or by heating in'an inert organic solvent.
  • Suitable as such are, e.g. hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as ;-methylene chloride, and lower ketones such as acetone or methyl ethyl ketone.
  • the reaction can, in general, be
  • such agents e.g. alkali metal alcoholates and alkali metal hydroxides, can beadded.
  • inorganic bases or salts such as, e.g. an alkali hydroxide, alkali acetate, alkali hydrogen carbonate, alkali carbonate and alkali phosphate, such assodium hydroxide,.sodium acetate,
  • organic bases are also suitable such as, e.g. pyridine, trimethylor triethylamine, diisopropylamine,
  • N-alkali metal derivatives of these compounds such as e.g. sodium
  • Thestarting compounds of formula II are, for their part, new compounds. They can beproduced, e.g. by
  • Suitable reactive derivatives of a sulfonic acid of formula V are halides, especially chlorides and anhydrides of formula Va,
  • starting materials of formula II are obtained by reacting substituted p-(aminoalkyl)- benzenesulfonamides of formula VII,
  • the preparation of the starting compounds of formula III and of formula IV is carried out using the generally known preparationmethods for isocyanates, and carbamic acid derivatives and thiocarbamic acid derivatives, respectively.
  • compositions comprised by the present invention are readily available by allowing to reach a compound of formula I with a suitable acid and isolating the salt by conventional methods.
  • physiologically harmless inorganic or organic acids such as, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, lactic acid, succinic (Vlll acid, tartaric acid and maleic acid.
  • hypoglycemic sulfonyl ureas such as, e.g.
  • p-toluene-sulfonylbutyl urea p-chlorobenzenesulfonylpropyl urea
  • p[2(2- methoxy-S-chlorobenzamido)-ethyI]-phenylsulfonylcyclohexy] urea can be used.
  • the compounds of the present invention have been found to have valuable hypoglycemic activities in warm-blooded animals upon oral or parenteral administration. These activities are illustratively demonstrated in rats by orally administering the test compound to groups of five to six animals which have not been fed for 24 hours. Blood samples are taken from the vein, and the blood sugar content is determined according to the method of Hagedom-Jenson with an auto-analyzer.
  • the compounds of formula I. and the pharmaceutically acceptable salts thereof are preferably administered orally in a daily dosage of from 10 to 400 mg/kg of bodyweight.
  • the dosage must necessarily be adjusted to the age, size and condition of the particular host being treated.
  • the compounds of the invention are provided in dosage unit forms including'for example, tablets, capsules, dragees, powders, syrups, elixits, and the like.
  • Suitable dosage units such as dragees or tablets, preferablycontain 10-200 mg of an active substance according to the invention, whereby the content of ac tive substance is. 20-80 percent by weight.
  • Tablets and dragees are produced by combining the active substance, e.g. with solid pulverulent-carriers such as lactose, saccharose, sorbitolor mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder, cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights.
  • solid pulverulent-carriers such as lactose, saccharose, sorbitolor mannitol
  • starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder, cellulose derivatives or gelatine
  • the tablets and dragee-cores are coated, e.g. with concentrated sugar solutions whichmay also contain, e. g. gum arabic, talcum and/or titanium dioxide; or. with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents.
  • Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.
  • suitablev 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 preferably contain the active substance as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate and, optionally, stabilizers such as sodium metabisulfite (Na S O or ascorbic acid.
  • the active substance is n-propylisocyanate, dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby stabilizers may also be added.
  • EXAMPLE 1 a An amount of 39.8 g of l-[p-(2-aminoethyl)-phenyl sulphonyl] -2-imino-3-n-butylimidazolidinedihydrochloride is dissolved in ml of water, and the base liberated with ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of npropylisocynate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate.
  • the obtained oil (free base) is DIS- SOLVED in alcohol, and made acidic with saturated alcoholic hydrochloric acid.
  • l-[p-(2-aminoethyl)- phenylsulphonyl]-2-imino-3-butyl-imidazolidine dihydrochloride precipitates, M.P. 23 l-233.
  • EXAMPLE 2 In an analogous manner to Example 1 are obtained: from 38.4 g of 1-[p-(2-amino-ethyl)-phenylsulphonyl]- 2-imino-3-isopropyl-imidazolidine-dihydrochloride and 12.5 g of cyclohexyl-isocyanate the l-[p-(2- (cyclohexyl-ureido)-ethyl)-phenylsulphonyl]-2-imino- 3-isopropyl-imidazolidine, M.P. 158-l 58.
  • EXAMPLE 4 a 38.4 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-n-propyl-imidazolidine dihydrochloride are dissolved in ml of water; and the base is liberated with ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 12.5 g of cyclohexylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate.
  • the obtained cloudy solution is rendered alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation.
  • the obtained oil (free base) is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid.
  • EXAMPLE 5 a 39.8 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-isobutyl-imidazolidine dihydrochloride are dissolved in 100 ml of water, and the base liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of n-propylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. The 1-[p-(2- (3 -n-propylureido)-ethy1)-pheny1sulphonyl]-2-imino- 3-isobutyl-imidazolidine melts at 154156.
  • the obtained cloudy solution is made alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation.
  • the obtained oil (free base) is dissolved in alcohol and made acid with saturated alcoholic hydrochloric acid.
  • EXAMPLE 6 In an analogous manner to Example 4 is obtained, starting with 39.8 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-isobutyl-imidazolidinehydrochloride with 12.5 g of cyclohexylisocyanate, 1- [p-( 2-( 3-cyclohexylureido )-ethyl )-phenylsulph0nyl ]-2 -imino-3-isobutyl-imidazolidine, M.P. (from acetyl acetate).
  • EXAMPLE 7 a 41.0 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclopentyl-imidazolidine-dihydrochloride are dissolved in ml of water, and the base is liberated with ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 5.7 g of methylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. 1- [p-(2-(3-methylureido)-ethyl)-phenylsulphonyl]-2- imino-3-cyclopentyl-imidazolidine melts at l291 30.
  • the obtained cloudy solution is made alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation.
  • the obtained oil (free base) is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid.
  • l-[p-(2aminoethyl)- phenylsulphonyl]-2-imino-3-cyc1opentylimidazolidinc-dihydrochloride, M.P. 270, position) precipitates.
  • EXAMPLE 9 a 42.4 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 9.9 g of n-butylisocyanate, and stirring is maintained for one hour. The reaction mixture is thenconcentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate.
  • the base is liberated with 150 ml of 2-n sodium hydroxethyl acetate.
  • the obtained oil (free base) is dissolved in a1- cohol, and made acid with saturated alcoholic hydrochloric acid.
  • imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol.
  • EXAMPLE 12 the base is liberated with 150 ml of 2-n sodium hydroxide solution.
  • the base is extracted with 3 times 250 ml of methylene chloride.
  • To the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of npropylisocyanate, and stirring is maintained for one hour.
  • the reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate.
  • the l-[p-(2-(3-n-propylureido)-ethyl phenylsulphonyl]-2-imino-3-n-butyl-4-methylimidazolidine melts at l09l 12.
  • EXAMPLE 15 Starting with 41.1 g of l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-n-butyl-4-methyl*imidazolidinedihydrochloride are obtained, analogously to Example 14, with 12.5 g of cyclohexylisocyanate, the l-[p-(2-(3- cyclohexylureido)-et hyl)-phenyl-sulphonyl]-2-irnino- 3-n-butyl-4-methyl-imidazolidine, M.P. 137138 (from ethyl acetate).
  • EXAMPLE 17 39.7 g of l-[p-(2-aminoethyl)-phenylsulphonyl]-2- imino-3-n-propyl-5-methyl-imidazolidine-dihydrochloric are dissolved in 100 ml of water,v and the base is liberated with 150 m1 of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 11.] g of cyclopentylisocyanate, and stirring is maintained for one hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline.
  • EXAMPLE 19 a 39.8 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-n-butyl-irnidazolidine-dihydrochloride are dissolved in ml of water, and the base is liberated with ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. T o the methylene chloride solution (dried with sodium sulphate) are added 14 g of 4-cyclohex-3-enylisothiocyanate, and stirring is maintained for 1 hour.
  • the reaction'mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate.
  • EXAMPLE 20 39.8 g of l[p-(2-aminoethyl)-phenylsulphony1]-2- imino-3-isobutyl-imidazolidine-dihydrochloride are dissolved in 100 m1 of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 9.9 g of n-butylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate.
  • EXAMPLE 21 a 4L0 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclopentyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 14.1 g of cyclohexylisothiocyanate, and stirring is maintained for 1 hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate.
  • EXAMPLE 22 a 42.4 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times- 250 ml of-methylene chloride. To the methylene chloride solution, (dried with sodium sulphate) are added 12.7 g of cyclopentylisothiocyanate, and stirring is maintained for one hour.
  • the reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate.
  • EXAMPLE 23 EXAMPLE 24 a. 39.8 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-n-butyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated tracted twice with ml of methylene chloride.
  • EXAMPLE 25 a 39.8 g of l [p-(2-aminoethyl)-phenylsulphonyl]-2- imino-3-n-butyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylarnine. At room temperature is then added dropwise the solution of 14.8 g.
  • EXAMPLE 26 a 39.8 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-isobutyl-imidazolidine dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylamine.
  • EXAMPLE 27 Analogously to Example 28 are obtained: from 39.6 g of l-[p-(Z-amino-ethyl)-phenylsulphonyll- 2-imino-3-n-butyl-imidazolidine-dihydrochloride and 15.0 g of 4-morpholinecar-bonylchloride the 1-[p-(2- (4-morpholinecarboxamido) ethyl)-phenylsulphonyl]- 2-imino-3-n-butyl-imidazolidine, M.P. 176 177.
  • EXAMPLE 2s a. 41.0 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclopentyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and thebase is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride.
  • EXAMPLE 29 39.7 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]-2- imino-3-n-butyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylamine. At room temperature is then added the solution of 15 g of 4- morpholinyl chloride in 100 ml of methylene chloride,
  • EXAMPLE 30 1,000 g of l-[p-(2( 3-butylureido)-ethy1)-pheny1 sulphonyl]-2-imino-3-cyc1ohexyl-imidazolidine are mixed with 500 g of lactose and 270 g of potato starch; the mixture is then moistened with an aqueous solution of 8.0 g of gelatine, and granulated through a sieve.
  • the tablets may be provided with grooves for more precise adjustment of the dosage amount
  • EXAMPLE 32 A granulate is prepared from 1,000 g of l-[p-(2-(3- buty1-thio-ureido)-ethyl)-phenyl-sulphonyl]-2-imino- 3-cyclohexyl-imidazolidine, 345.0 g of lactose and the aqueous solution of 6.0 g of gelatine. After drying, the granulate is mixed with 10.0 g of colloidal silicon dioxide, 40.0 g of talcum, 40.0 g of potato starch and 5.0 g
  • R is alkyl of one to six carbon atoms, allyl, cycloalkyl of five to eight carbon atoms or cycloalkenyl of five to eight carbon atoms;
  • R is hydrogen, ethyl or methyl
  • R is alkyl of one to six carbon atoms, cycloalkyl of at most eight carbon atoms, cycloalkenyl of at most eight carbon atoms, alkenyl of three to five carbon atoms or phenyl;
  • R is hydrogen, alkyl of one to six carbon atoms or phenyl
  • R and R together are a polymethylene chain of four to seven carbon atoms or morpholino;
  • X is oxygen or sulfur
  • n 2 or 3; or a pharmaceutically acceptable acid addition salt thereof.
  • a compound according to claim 1 which is l-[p- 2-( 3-n-butyl-2-thioureido )-ethyl )-phenylsulfonyl ]-2 imino-3-n-butyl-imidazolidine.
  • a compound according to claim 1 which is l-[p- (2 3-n-butylureido )-ethyl)-phenylsulfonyl ]-2-imino- 3-cyclohexyl-imidazolidine.
  • a compound according to claim 1 which is l-[p- 2-( 3-n-propylureido)-ethyl )-phenylsu]fonyl ]-2-imino- 3 4-methylcyclohexyl )-irnidazolidine.
  • a compound according to claim 1 which is l-[p- 2-( 3 -ethyl-2-thioureido )-ethyl )-phenylsulfonyl ]-2- imino-3-cyclopentylimidazolidine.

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Abstract

1-(P-Ureidoalkylphenylsulfonyl)-2-imino-imidazolidines and 1-(pthioureidoalkylphenylsulfonyl)-2-imino-imidazolidines being substituted at the imidazolidine and at the 3-position of the ureido moieties are prepared; these compounds and the pharmaceutically acceptable acid addition salts thereof have hypoglycemic activity; pharmaceutical compositions comprising said compounds and methods of producing hypoglycemic effects in mammals are provided; an illustrative embodiment is 1-(p-(2-(3-nbutyl-2-thioureido)-ethyl)-phenylsulfonyl)-2-imino-3-n -butylimidazolidine.

Description

United States Patent [191 Dietrich 1 Apr. 3, 1973 I54] DERIVATIVES OF P-AMINOALKYL BENZENESULFONAMIDES [75] Inventor:
land [73] Assignee: Ciba-Geigy Corporation, Ardsley,"
[22] Filed: Aug. 5, 1970 [2]] Appl. No.: 61,510
Dietrich Chem. Abst. Vol. 70, No. 47450g (I969). QDLASI Henri Dietrich, Arlesheim, Switzer- Dietrich Chem. Abst. Vol. 72, No. l2728t (I970).
QDLASI 1 Dietrich Chem. Abst. Vol. 72, No. 3l793b (1970).
QDLASI V Dietrich Chem. Abst. Vol. 71, No. 9l476q (I969). QDLASI Yoshitomi Pharmaceutical Industries Chem. Abst. Vol. 62, column 16135 (1965) QDLASI Schotte et al. Chem. Abst. Col. 22, pages 1759-1760 Primary Ex aminer-Natalie Trousof Att0rney-Karl F. .Iorda and Bruce M. Collins 57 ABSTRACT I -(p-Ureidoalkylphenylsulfonyl)-2-iminoimidazolidines and I-(p-thioureidoalkylphenylsulfonyl)-2-imino-imidazolidines being substituted at the im'idazolidine and at the 3-position of the ureido moieties are prepared; these compounds and the pharmaceutically acceptable acid addition salts thereof have hypoglycemic activity; pharmaceutical compositions comprising said compounds and methods of producing hypoglycemic effects in mammals are provided; an illustrative embodiment is 1-[p-(2-(3-nbutyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3- n-butyl-imidazolidine.
' 6 Claims, No Drawings DERIVATIVESOF P-AMINOALKYL BENZENESULFONAMIDES The present invention relates to new derivatives ofpaminoalkyl benzenesulfonamides, processes for their preparation, to medicaments containing'the new compounds and their use.
More particularly, the present invention concerns compounds of the formula I,
wherein 1 R is alkyl having oneito six carbon atoms, allyl, cycloalkyl having five to eight carbon atoms, or cycloalkenyl having five to eight carbon atoms; R is hydrogen, ethyl or methyl; R is alkyl having one to-six carbon atoms, cycloalkyl having at. most eightcarbon atoms, cycloalkenyl having at most eightcarbon atoms, alkenyl having- .butyl, sec'.butyl,=tert.butyl,* isobutyl,-pentyl, isopentyl, 4
2,2-dimethylpropyl, l-methylbutyl, l-ethylpropyl, 1,2
dimethylpropyl, n-hexyl, methylpentyhz'dimethylbutyl, or-ethylbutyl; as cycloalkyl; R, can denote cyclopentyl, which can be optionally substituted by alkyl having one-three carbon atoms; cyclohexyl, which can besubstituted by ethyl or methyl; cycloheptyl, optionally substituted by methyl; as well ascyclooctyl; as cycloalkenyl, R, can denote-2-cyclopenten-l yl, 2-cyclohexen-lyl, 3-cyclohexen l yl, 2-methyl-2-cyclohexen l-yl, 3--
cycloheptenl -yl, or a cyclooctenyl group.
The substituent R embraces the'same alkyl, cycloal-- kyl or cycloalkenyl group'skas stated'under' R asalkenyl, R can denoteallyLfl -methylallyl,2-methylallyl,2 or 3-butenyl, or 2-, '3- or 4-pentenyl.
Compounds of formula, I are produced compound of formula ll,
(Ill
wherein v R R and m have the meaning-given under formula I, with an isocyanate of formula II],
1 by reacting a R N C X (Ill) wherein R and X have the meaning given under formula I; or
, with a reactive derivative of a carbamic acid or thiocarbamic acid of formula IV,
Ra X
ll /N-C0H R4 (1v) wherein R3, R and X have the meaning given under formula I; and, optionally, converting the obtained reactionv products into the salt of an inorganic or organic acid. Suitable as reactive derivatives of a carbarnic acid or thioca'rbamic acid of formula III are, e.g. the halides,
especially the chlorides, the lower alkyl esters, particularly'the methyl or ethyl esters, the phenyl esters, the amides, the lower monoor dialkylamides, in particular the N-methyl amides and the N,N-dirnethylamides, the diphenylamides, also the N-acylamides such as, e.g. the
, acetylamides and the benzoylamides. I
w The reaction is performed, e.g. at room temperature, or by heating in'an inert organic solvent. Suitable as such are, e.g. hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as ;-methylene chloride, and lower ketones such as acetone or methyl ethyl ketone. The reaction can, in general, be
carried out without the addition of condensing agents;
optionally, however, such agents, e.g. alkali metal alcoholates and alkali metal hydroxides, can beadded.
A halide of a carbarnic acid or thiocarbamic acid of formula IV is reacted according to the invention,
preferably in the presence of an acid binding agent. As such it is possible to use inorganic bases or salts, such as, e.g. an alkali hydroxide, alkali acetate, alkali hydrogen carbonate, alkali carbonate and alkali phosphate, such assodium hydroxide,.sodium acetate,
sodium hydrogen carbonate, sodium carbonate and sodium phosphate, or the corresponding potassium compounds. It is also possible to usecalcium oxide, calcium carbonate, as well as calcium phosphate and magnesium, carbonate. 'In addition to inorganic bases or salts, organic bases are also suitable such as, e.g. pyridine, trimethylor triethylamine, diisopropylamine,
solvent. r
Instead of amines of formula II, it is also possible to use for the reaction (according to the invention) with a carbamic or thiocarbamic acid chloride, N-alkali metal derivatives of these compounds, suchas e.g. sodium,
potassium or lithium derivatives; -Thestarting compounds of formula II are, for their part, new compounds. They can beproduced, e.g. by
reactinga reactive derivative of a sulfonic acid of form has the meaning given in formula I, with 2-amino-.
. 2-imidazoline derivatives of the formula VI,
or collidine. Added in excess, these can also be used as wherein R and R have the meaning given under formula I;
and afterwards hydrolytically splitting-off the protective acyl group (RCO). The N-acyl compounds derived from formula II, obtained as intermediate product, have likewise not been described hitherto in the literature. Suitable reactive derivatives of a sulfonic acid of formula V are halides, especially chlorides and anhydrides of formula Va,
1i 2 (Va) wherein R has the meaning given under formula V. The anhydrides of formula Va can be obtained in a simple manner by the reaction of corresponding substituted sulfonic acid halides with salts of correspondingly substituted sulfonic acids.
Using a further process, starting materials of formula II are obtained by reacting substituted p-(aminoalkyl)- benzenesulfonamides of formula VII,
wherein m has the meaning given under formula I, with substituted N-(Z-bromoalkyl)-cyanoamides in an alkaline medium. Compounds of formula VII are, in turn, obtained substantially in accord with E. Miller, et al., J .Am.Chem.Soc., 62,2099 (1940). Thus, for example, N-ace'tylphenethylamine is reacted with chlorosulfonic acid. The resulting sulfonylchloride is converted to the corresponding sulfonamide with aqueous ammonia and finally, the acet-yl group is hydrolyzed to give the p-(B- aminoethyl)-benzenesulfonamide.
The preparation of the starting compounds of formula III and of formula IV is carried out using the generally known preparationmethods for isocyanates, and carbamic acid derivatives and thiocarbamic acid derivatives, respectively.
Pharmaceutically acceptable salts comprised by the present invention are readily available by allowing to reach a compound of formula I with a suitable acid and isolating the salt by conventional methods.
For formation of pharmaceutically acceptable salts it is possible to use physiologically harmless inorganic or organic acids, such as, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, lactic acid, succinic (Vlll acid, tartaric acid and maleic acid. Also hypoglycemic sulfonyl ureas such as, e.g. p-toluene-sulfonylbutyl urea, p-chlorobenzenesulfonylpropyl urea, and p[2(2- methoxy-S-chlorobenzamido)-ethyI]-phenylsulfonylcyclohexy] urea can be used.
The compounds of the present invention have been found to have valuable hypoglycemic activities in warm-blooded animals upon oral or parenteral administration. These activities are illustratively demonstrated in rats by orally administering the test compound to groups of five to six animals which have not been fed for 24 hours. Blood samples are taken from the vein, and the blood sugar content is determined according to the method of Hagedom-Jenson with an auto-analyzer. Thus, it is shown that l-[p-( 2-(3-nbutyl-2-thioureido )-ethyl )-phenylsulfonyl -2-imino- 3 n-butyl-imidazolidine on oral administration in amounts from about 20 to about 400 mg/kg of bodyweight has a pronounced blood sugar lowering effect.
Similar effects are found with other compounds of the invention.
The compounds of formula I. and the pharmaceutically acceptable salts thereof, are preferably administered orally in a daily dosage of from 10 to 400 mg/kg of bodyweight. The dosage must necessarily be adjusted to the age, size and condition of the particular host being treated.
For their intended use the compounds of the invention are provided in dosage unit forms including'for example, tablets, capsules, dragees, powders, syrups, elixits, and the like.
Suitable dosage units such as dragees or tablets, preferablycontain 10-200 mg of an active substance according to the invention, whereby the content of ac tive substance is. 20-80 percent by weight. Tablets and dragees are produced by combining the active substance, e.g. with solid pulverulent-carriers such as lactose, saccharose, sorbitolor mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder, cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights. The tablets and dragee-cores are coated, e.g. with concentrated sugar solutions whichmay also contain, e. g. gum arabic, talcum and/or titanium dioxide; or. with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance. I
Other suitablev 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 preferably contain the active substance as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate and, optionally, stabilizers such as sodium metabisulfite (Na S O or ascorbic acid. In soft capsules, the active substance is n-propylisocyanate, dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby stabilizers may also be added.
The following examples will serveto further typify the nature of the present invention, but should not be construed as a limitation on the scope thereof. Temperatures are given in degrees Centigrade.
EXAMPLE 1 a. An amount of 39.8 g of l-[p-(2-aminoethyl)-phenyl sulphonyl] -2-imino-3-n-butylimidazolidinedihydrochloride is dissolved in ml of water, and the base liberated with ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of npropylisocynate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. 1-[p-( 2-( 3-n-propylureido )-ethyl-phenylsulphonyl]-2-imino-3-n-butyl-imidazolidine melts at b. The starting material: l-[p-(2-aminoethy1)-phenylsulphonyl]-2-imino-3-butylimidazolidinedihydrochloride, is obtained by two processes:
1. An amount of 36.65 g of 1-[p-(2-acetaminoethyl)- phenylsulphonyl]-2-imino-3-butyl-imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-butylimidazolidinedihydrochloride crystallizes out in the cold state, M.P. 23 l-233. dissolved 1 p-( 2-Acetamidoethyl )-phenylsulphonyl]-2-imino- 3-butyl-imidazolidine can be produced as follows:
To a solution of 8.5 g of sodium hydroxide in 85 ml of water are added 17.8 g of l-butyl-2- iminoimidazolidine-hydrochloride. To the obtained clear solution is added a solution of 26.6 g of p-(2- acetamidoethyl)-benzenesulphochloride in 100 ml of acetone, whereby a rise in temperature occurs. The mixture is subsequently heated for half an hour to 90, and then concentrated to dryness in vacuo. The residue is recrystallized from ethyl acetate. The pure 1-[p-(2- acetamidoethyl)-phenylsulphonyl]-2-imino+3-butylimidazolidine melts at 130131.
The 1-[p-(2-acetamidoethyl)-phenylsulphonyl]-2- imino-imidazolidines required in the following examples for the production of the starting material are obtained in an analogous manner, by the reaction of p- (2-acetamidoethyl)-benzenesulphochloride with correspondingly substituted 2-imino-imidazolidines. 2. A mixture of 100 ml of dimethylsulphoxide, 11.2 g of powdered potassium hydroxide, 23.65 g of p-(2- aminoethyl)-benzenesulphonamide hydrochloride [Lit.: E.Mi1ler et al., J.Amer.Chem.Soc.62, 2101, (1940)]and 16 g of N-(2-chloroethyl)-N-butylcyanimide is heated, whilst being stirred, for 1 hour in an oil bath at 1 After cooling, the mixture is poured on to water The obtained cloudy solution is rendered alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The obtained oil (free base) is DIS- SOLVED in alcohol, and made acidic with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, l-[p-(2-aminoethyl)- phenylsulphonyl]-2-imino-3-butyl-imidazolidine dihydrochloride precipitates, M.P. 23 l-233.
EXAMPLE 2 In an analogous manner to Example 1 are obtained: from 38.4 g of 1-[p-(2-amino-ethyl)-phenylsulphonyl]- 2-imino-3-isopropyl-imidazolidine-dihydrochloride and 12.5 g of cyclohexyl-isocyanate the l-[p-(2- (cyclohexyl-ureido)-ethyl)-phenylsulphonyl]-2-imino- 3-isopropyl-imidazolidine, M.P. 158-l 58.
from 42.5 g of 1-[p-(2-amino-ethyl)-phenylsulphonyl]- 2-imino-3-n-butyl-4-ethyl-imidazolidinedihydrochloride and 12.5 g of cyclohexyl-isocyanate the l-[p-(2-( cyclohexyl-ureido)-ethyl)-phenylsulphonyl]-2-imino-3-n-butyl-4-ethyl-imidazolidine, M.P. 98 99. from 43.7 g of 1-[p-(2-amino-propyl)-phenylsulphonyl1-2imino-3-cyclohexyl-imidazolidinedihydrochloride and 12.5 g cyclohexyl-isocyanate the 1 [p-( 2-( cyclohexyl-ureido )-propy1 )-phenylsulphonyl1-2-imino-3-cyclohexyl-imidazolidine, M.P. 201 202 EXAMPLE 3 Starting with 39.8 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-n.butyl-imidazolidinedihydrochloride are obtained, analogously to Example 1, the following:
a. with 8.5 g of isopropylisocyanate, 1-[p-(2-(3- isopropylureido)-ethyl)-phenylsulphonyl]-2-imino-3- n-butyl-imidazolidine, M.P. 151152 (from ethyl acetate);
b. with 9.9 g of n-butylisocyanate, 1-[p-(2-(3-n-butylureido)-ethyl)-phenylsu1phonyl]-2-imino-3-n-buty1- imidazolidine, M.P. l58l59 (from ethyl acetate);
c. with 11.5 g of n-butylisothiocyanate, 1-[p-( 2-(3-nbutyl-2-thioureido)-ethyl)-phenylsulphonyl1-2-imino- 3-n-butyl-imidazolidine, M.P.- 183l84 (from ethyl acetate);
(1. with 11.1 g of cyclopentylisocyanate, 1-[p-(2-(3- cyclopentylureido )-'ethyl )-phenylsulphonyl l-2-imino- B-n-butyI-imidazolidine, M.P. 176-177 (from ethyl acetate);
e. with 11.9 g of phenylisocyanate, 1-[p-(2-(3- phenyureido)-ethyl)-phenylsulphonyl]-2-imino-3-n butyl-imidazolidine hemihydrate, M.P. 210-21 1 (from ethyl acetate);
f. with 13.5 g of phenylisothiocyanate, 1-[p-(2-(3- phenyl-2-thioureido)-ethyl)-phenylsulphonyl]-2- imino-3-n-butyl-imidazolidine containing one-fourth mole of hydrogen, M.P. 195196 (from ethyl acetate); Y
EXAMPLE 4 a. 38.4 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-n-propyl-imidazolidine dihydrochloride are dissolved in ml of water; and the base is liberated with ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 12.5 g of cyclohexylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. The 1-[p-(2- 3-cyclohexylureido )-ethyl )-phenylsu1phonyl -2- imino-3-n-propyl-imidazolidine melts at l85l 86.
b. The starting material: l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-propyl-imidazolidine dihydrochloride, is produced by two processes:
1. An amount of 35.2 g of l-[p-(2-acetaminoethyl)- phenyl-sulphonyl]-2-iinino-3-propyl-imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved a in alcohol. The l[p-( 2-aminoethyl)- benzenesulphonyl ]-2-imino-3-propyl-imidazolidine dihydrochloride, M.P. 255256, crystallizes out in the cold state. 2. A mixture of 100 ml of dimethylsulphoxide, l 1.2 g of powdered potassium hydroxide, 23.65 g of p-(2-aminoethyl)-phenylsulphonamide hydrochloride [Lit.: E.Miller et al. J.Amer.Chem.Soc.62, 2101, 1940)] and 16 g of N-(2- chloroethyl)-N-propyl-cyanamide is heated, whilst being stirred, for 1 hour in an oil-bath at 1 10. After the mixture has cooled, it is poured on to water. The obtained cloudy solution is rendered alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The obtained oil (free base) is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-propyl-imidazolidine dihydrochloride, M.P. 255-256, precipitates.
EXAMPLE 5 a. 39.8 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-isobutyl-imidazolidine dihydrochloride are dissolved in 100 ml of water, and the base liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of n-propylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. The 1-[p-(2- (3 -n-propylureido)-ethy1)-pheny1sulphonyl]-2-imino- 3-isobutyl-imidazolidine melts at 154156.
b. The starting material: 1-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-isobutyl-imidazolidinedihydrochloride monohydrate, is produced by two processes:
1. An amount of 36.65 g of l-[p-(2-acetaminoethyl)- phenysulphonyl]-2-imino-3-isobutyl-imidazolidine is dissolved in 370 ml of 2-n. hydrochloric acid, and the solution is refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1-[p-(2-aminoethyl)- benzenesulphonyl]-2-imino-3-isobutyl-imidazolidinedihydrochloride monohydrate, M.P. 151-152, crystallizes out in the cold state.
2. A mixture of 100 ml ofdimethylsulphoxide, 1 1.2 g of powdered potassium hydroxide, 23.65 g of p-(2- aminoethyl)-benzenesulphonam'ide hydrochloride [Lit.: E.Miller et al. J.Amer.Chem.Soc. 62, 2101, (1940)]and 20.5 g of N(2-bromoethyl)-N-isobutylcyanamide is heated, whilst being stirred, for 1 hour in an oil-bath at 1 10. After the mixture has cooled, it is poured on to water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The obtained oil (free base) is dissolved in alcohol and made acid with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, 1-[p-(2- aminoethyl)-phenylsulphonyl]-2-imino-3-isobutyl- 8 imidazolidine-dihydrochloride monohydrate, M.P. 15 1-152, precipitates.
EXAMPLE 6 In an analogous manner to Example 4 is obtained, starting with 39.8 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-isobutyl-imidazolidinehydrochloride with 12.5 g of cyclohexylisocyanate, 1- [p-( 2-( 3-cyclohexylureido )-ethyl )-phenylsulph0nyl ]-2 -imino-3-isobutyl-imidazolidine, M.P. (from acetyl acetate).
EXAMPLE 7 a. 41.0 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclopentyl-imidazolidine-dihydrochloride are dissolved in ml of water, and the base is liberated with ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 5.7 g of methylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is then concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. 1- [p-(2-(3-methylureido)-ethyl)-phenylsulphonyl]-2- imino-3-cyclopentyl-imidazolidine melts at l291 30.
b. The starting material: 1-[p-(2-aminoethyl)phen ylsulphonyl]-2 imino-3-cyclopentyl-imidazolidinedihydrochloride, is obtained by two processes:
1. An amount of 37.8 g of 1-[p-(2-acetaminoethy1)- phenylsulphonyl]-2-imino-3-cyclopentyl-imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution is refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The l-[p-(2-aminoethyl)- benzenesulphonyl]-2-imino-3-cyclopentylimidazolidine-dihydrochloride, M.P. 270, crystallizes out in the cold state.
2. A mixture of 100 ml of dimethylsulphoxide, l 1.2 g of powdered potassium hydroxide, 23.65 g of p-(2- aminoethyl)-phenylsulphonamide-hydrochloride [Lit.: E.Miller et al. J.Amer.Chem.Soc. 62, 2101, (1940)] and 17.2 g of N-(2-chloroethyl)-N-cyclopentyl-cyanamide is heated, whilst being stirred, for 1 hour in an oil bath at 1 10. After the mixture has cooled, it is poured on to water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The obtained oil (free base) is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, l-[p-(2aminoethyl)- phenylsulphonyl]-2-imino-3-cyc1opentylimidazolidinc-dihydrochloride, M.P. 270, position) precipitates.
(decom- EXAMPLE 8 Analogously to Example 7 is obtained, starting with 41.0 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]-2- imino-3-cyclopentyl-imidazolidine-dihydrochloride, the following:
a. with 9.9 g of n-butylisocyanate, l-[p-(2-(3-n-butylureido)-ethyl)-phenylsulphonyl]-2-imino-3- cyclopentyl-imidazolidine, M.P. l 34l 36 (from ethyl acetate).
EXAMPLE 9 a. 42.4 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 9.9 g of n-butylisocyanate, and stirring is maintained for one hour. The reaction mixture is thenconcentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. 1 [p-( 2-( 3-n -butylureido )-ethyl )-phenylsulphonyl ]-2- imino-3-cyclohexyl-imidazolidine melts at l6l.5
b. The starting material: l-{p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclohexyl-imidazolidinedihydrochloride, is obtained by two processes:
1. An amount of 39.2 g of l-[p-(2-acetaminoethyl)- phenylsulphonyl]-2-imino-3-cyclohexyl-imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution is refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The 1-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclohexyl-imidazolidinedihydrochloride, M .P. 247250, crystallises out in the cold state. 2. A mixture of 100 ml of dimethylsulphoxide, 11.2 g of powdered potassium hydroxide, 23.65 g of p-( 2-aminoethyl )-benzenesulphonamide hydrochloride [Lit.: E.Miller et al, J.Amer.Chem.Soc.62, 2101, (1940)] and 23.1 g of N- (2-bromoethyl)-N-cyclohexylcyanamide is heated, whilst being stirred, for 1 hour in an oil-bath at 110. After the mixture has cooled, it is poured on to water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride, and extracted three times with methylene chloride; the organic phases are dried over EXAMPLE 1 1 g 43.8 g of l-[p-(2-aminoethyl)-phenylsulphonyl]-2- imino-3-(4-methylcyclohexyl)-imidazolidinedihydrochloride are dissolved in 100 ml of water, and
the base is liberated with 150 ml of 2-n sodium hydroxethyl acetate. The l-[p-(2-(3-n-propylureido)-ethyl) phenylsulphonyl]-2-imino-3-(4-methylcyclohexyl)- V phenylsulphonyl]-2-imino-3-(4-methylcyclohexyl)- sodium sulphate, filtered and concentrated by evaporation. The obtained oil (free base) is dissolved in a1- cohol, and made acid with saturated alcoholic hydrochloric acid. As a result-of cooling and, if necessary, dilution withether, l [p -(2-aminoethyl)-phenylsulphonyl]-2-imino-3cyclohexyl-imidazolidinedihydrochloride, M.P. 247250, precipitates.
EXAMPLE 10 Starting with 42.4 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclohexyl-imidazolidinedihydrochloride, the following are obtained analogously to Example 9:
a. with 1 1.5 g of n-butylisothiocyanate, 1-[.p-( 2-(3-nbutyl2-thioureido)-ethyl)-phenylsulphony1]-2-imino- 3-cyclohexyl-imidazolidine, M.P. l86-l87 (from ethyl acetate);
b. with l 1.9 g of phenylisocyanate, l-[p-(2 -(3-phenyl-2-thioureido)-ethyl)-phenylsu1phonyl]-2-imino-3- cyclohexyl-imidazolidine, M.P. 2l0.53 212 (from ethyl acetate);
c. with 13.5 g of phenylisothiocyanate, l-[p-(2-(3- phenyl-2-thioureido)-ethyl)-phenylsulphonyl]-2- imino-3-cyclohexyl-imidazolidine, M.P. 188189 (from ethyl acetate).
imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The l-[p-(2- aminoethyl)-benzenesulphonyl]-2-imino-3-(4-methylcyclohexyl)-imidazolidine-dihydrochloride, M.P. 260,
- (with decomposition), crystallises out in the cold state.
b. A mixture of ml of dimethylsulphoxide, 1 1.2 g of powdered potassium hydroxide, 23.65 g of p-(2- aminoethyl)-benzenesulphonamide-hydrochloride [Lit.: E. Miller et al, J. Amer.Chem.Soc. 62, 2101, (1940)]and 200 g of 2-chloroethyl-(4-methylcyclohexyl-cyanamide is heated, whilst being stirred, for 1 hour in an oil-bath at 1 10. After the mixture has cooled, it is poured on to water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide solution, saturated with sodium chloride,
and extracted three times with methylene chloride; the' organic phases are dried over sodium sulphate, filtered, and concentrated by evaporation. The obtained oil (free base) .is dissolved in alcohol, and made acid with saturated alcoholic hydrochloric acid. As a result of cooling and, if necessary, dilution with ether, l-[p-(2- aminoethyl)-benzenesulphonyl]-2-imino-3-(4-methylcyclohexyl)-imidazolidine-dihydrochloride, M.P. 260 (with decomposition) precipitates.
EXAMPLE 12 the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 8.5 g of npropylisocyanate, and stirring is maintained for one hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. The l-[p-(2-(3-n-propylureido)-ethyl phenylsulphonyl]-2-imino-3-n-butyl-4-methylimidazolidine melts at l09l 12.
b. The starting material: l-[p-(2-aminoethyl)-phenylsulphonyl ]-2-imino-3-butyl-4-methyl-imidazolidinedihydrochloride is produced by the following process:
An amount of 38.0 g of 1-[p-(2-acetaminoethyl)- phenylsulphonyl]-2-imino-3-butyl-4-methylimidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution is refluxed for 6 hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The l-[p-(2-aminoethyl )-phenylsulphonyl]-2-imino-3-butyl-4-methylimidazolidine-dihydrochloride, M.P. 240 (decomposition), crystallises out in the cold state.
EXAMPLE 15 Starting with 41.1 g of l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-n-butyl-4-methyl*imidazolidinedihydrochloride are obtained, analogously to Example 14, with 12.5 g of cyclohexylisocyanate, the l-[p-(2-(3- cyclohexylureido)-et hyl)-phenyl-sulphonyl]-2-irnino- 3-n-butyl-4-methyl-imidazolidine, M.P. 137138 (from ethyl acetate).
EXAMPLE 16 I 3-isoamyl-ureido )-ethyl) phenylsulphonyl]-2-imino-3- n-butyl-S-methyl-imidazolidine melts at 1 17 1 18.
b. The starting material: 1-[p-(2-a.minoethyl)-phenylsulphonyl]-2-imino-3-butyl-5-methyl-imidazolidinedihydrochloride is produced, analogously to Example 14 (b), from 38.0 g of l-[p-(2-acetaminoethyl)-phenylsulphonyl]-2-imino-3-butyl-5-methyl-imidazolidinedihydrochloride, MP. 25 5 "257.
EXAMPLE 17 39.7 g of l-[p-(2-aminoethyl)-phenylsulphonyl]-2- imino-3-n-propyl-5-methyl-imidazolidine-dihydrochloric are dissolved in 100 ml of water,v and the base is liberated with 150 m1 of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 11.] g of cyclopentylisocyanate, and stirring is maintained for one hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline. residue recrystallized from 14 ethyl acetate. The l-[p-(2-(3-cyclopentylureido)- ethyl )-phenylsulphonyl]-2-irnino-3-n-propyl-5-methylimidazolidine melts at l37138.
The starting material: l-[p-(2-aminoethyl)- benzenesulphonyl]-2-imino-3-propyl-5-methylimidazolidine-dihydrochloride is produced as follows:
An amount of 36.6 g of l-[p-(2-acetaminoethyl)- phenylsulphonyl]-2-imino-3-propyl-5-methylimidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution is refluxed for 6-hours. The solution is then concentrated to dryness in vacuo, and the obtained oil dissolved in alcohol. The l-[p-(2-aminoethyl )-benzenesulphonyl]-2-imino-3-propyl-5-methylimidazolidine-dihydrochloride, M.P. 241-242, crystallis'es out in the cold state.
EXAMPLE 18 imidazolidine melts at 995 100.5.
' The starting material: l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-n-propyl-5-methylimidazolidine-dihydrochloride is produced analogously to Example 17.
EXAMPLE 19 a. 39.8 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-n-butyl-irnidazolidine-dihydrochloride are dissolved in ml of water, and the base is liberated with ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. T o the methylene chloride solution (dried with sodium sulphate) are added 14 g of 4-cyclohex-3-enylisothiocyanate, and stirring is maintained for 1 hour. The reaction'mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. The 1 [p-( 2-( 3-cyclohex-3-enyl-2-thioureido ethyl)-phenylsulphonyl]-2-imino-3-n-butylimidazolidine melts at 182l 83.
b. The starting material: l-[p (2-aminoethyl)-phenylsulphonyl]-2-irnino-3-n-butyl-imidazolidinedihydrochloride is obtained accordingto the instructions given in Example 1(b).
EXAMPLE 20 39.8 g of l[p-(2-aminoethyl)-phenylsulphony1]-2- imino-3-isobutyl-imidazolidine-dihydrochloride are dissolved in 100 m1 of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 9.9 g of n-butylisocyanate, and stirring is maintained for 1 hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. The l-[p-(2- 3 -ncbutylureido )-ethyl )-phenylsulphonyl ]-2-imino-3- isobutyl-imidazolidine melts at 144 144.5".
The starting material: l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-isobutyl-imidazolidinedihydrochloride is produced analogously to Example 5(b).
EXAMPLE 21 a. 4L0 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclopentyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 14.1 g of cyclohexylisothiocyanate, and stirring is maintained for 1 hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. The l-[p-(2-(3-cyclohexyl-2-thioureido )-ethyl )-phenylsulphonyl ]-2-imino-3cyclopentylimidazolidine melts at 2 l 52 1 6.
b. The starting material: I-[p-(Z-aminOethyD-phenylsulphonyl]-2-imino-3-cyclopentyl-imidazolidinedihydrochloride is obtained according to the instructions given in Example 7(b).
EXAMPLE 22 a. 42.4 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times- 250 ml of-methylene chloride. To the methylene chloride solution, (dried with sodium sulphate) are added 12.7 g of cyclopentylisothiocyanate, and stirring is maintained for one hour. The reaction mixture is thereupon concentrated in vacuo, and the crystalline residue recrystallized from ethyl acetate. The 1-[p-(2-(3-cyclopentyl-2-thioureido)-ethyl)-phenylsulphonyl]-2-imino-3-cyclohexylimidazolidine melts at 206207.
b. The starting material: l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclohexyl-imidazolidinewith 150 ml of 2-n sodium hydroxide solution. It is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylamine. At room temperature are then added the solution of 23.2 g of diphenylcarbamic acid chloride in 100 ml of methylene chloride, and stirring is maintained for 4 hours at room temperature. The whole is then washed twice with ml of water each time. The aqueous phases are exdihydrochloride is obtained according to the instructions given in Example 9(b).
EXAMPLE 23 EXAMPLE 24 a. 39.8 g of l-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-n-butyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated tracted twice with ml of methylene chloride. The combined methylene chloride phases yield, after being dried with sodium sulphate, filtered, and concentrated by evaporation, l-[p(2-(3,3-diphenyl-ureido)-ethyl)- phenylsulphonyl]-2-imino-3-n-butyl-imidazolidine which, recrystallized from ethyl acetate, melts at 96.5 98.
b. The starting material: l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-n-butyl-imidazolidinedihydrochloride is obtained according to the instructions given in Example 1(b).
EXAMPLE 25 a. 39.8 g of l [p-(2-aminoethyl)-phenylsulphonyl]-2- imino-3-n-butyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylarnine. At room temperature is then added dropwise the solution of 14.8 g. of piperidine carbonyl chloride in 100 ml of methylene chloride, and the whole is stirred for 4 hours at room temperature; it is then washed twice with 30 ml of water each time. The aqueous phases are extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases yield, after drying with sodium sulphate, filtration, and concentration by evaporation, l-[p-( 2-( l-piperidinecarboxamido)- ethyl)-phenylsulphonyl]-2-imino-3-n-butylimidazolidine which, recrystallized from ethyl acetate, melts at 179.5 180.5".
b. The starting material: l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-n-butyl-imidazolidinedihydrochloride is obtained according to the instructions given in Example 1(b).
EXAMPLE 26 a. 39.8 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-isobutyl-imidazolidine dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylamine. At room temperature are then added the solution of 9.8 g of dimethylcarbamic acid chloride in 100 ml of methylene chloride, and the whole is stirred for 4 hours at room temperature; it is then washed twice with 30 ml of water each time. The aqueous phases are extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases yield, after being dried with sodium sulphate, filtered, and concentrated by evaporation, l-[p-(2-(3,3-dimethylureido)-ethyl)- phenylsulphonyl]-2-imino-3-isobutyl-imidazolidine which, recrystallized from ethyl acetate, melts at b. The starting material: 'l [-p-(2+aminoethyl)-phenylsulphonyl]-2imino-3-isobutyl-imidazolidinedihydrochloride is obtained according to the instructions given in Example (b). I 4
EXAMPLE 27 Analogously to Example 28 are obtained: from 39.6 g of l-[p-(Z-amino-ethyl)-phenylsulphonyll- 2-imino-3-n-butyl-imidazolidine-dihydrochloride and 15.0 g of 4-morpholinecar-bonylchloride the 1-[p-(2- (4-morpholinecarboxamido) ethyl)-phenylsulphonyl]- 2-imino-3-n-butyl-imidazolidine, M.P. 176 177.
from 42.5 g of l-[p (Lamino-ethyl)-phenylsulphonyl]- 2-imino-3-cyclohexyl-imidazolidine-dihydrochloride and 13.9 g of N-n-butyl-N-methylcarbamic acid chloride the 1-[p-(2-(3-n-butyl-13-methylureido)- ethyl )-phenylsulphonyl]-2-imino-3-cyc1ohexylimidazolidine, M.P. 134 136.
from 39.6 g of l-[p-( 2-arnino-ethyl)-pheny1sulphonyl]- 2-imino-3-n-butyl-imidazolidinc-dihydrochloride and 13.9 g of N-n-buty1-N-methyl-amino-carbonylchloride the 1 [p-( 2-( 3 ,3-n-butyl-methylureido )-ethyl)-phenylsulphonyl]-2-imino-3-n-butyl-imidazolidine, M.P. 136 137.
EXAMPLE 2s a. 41.0 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]- 2-imino-3-cyclopentyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and thebase is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) is added dropwise,.at room temperature, the solution of 23.2 g of diphenylcarbamic acid chloride in 100 ml of methylene chloride; the whole is then stirred for 4 hours at room temperature, and afterwards washed twice with 30 ml of water each time. The aqueous phase is extracted twice with 100 m1 of methylene chloride. The combined methylene chloride phases yield, after being dried with sodium sulphate, filtered, and concentrated byevaporation, 1- [p-( 2-( 3 3 -diphenylurei do )-ethyl )-phenylsulphonyl] -2- imino-3-cyclopentyl-imidazolidine-hydrochloride which, recrystallized from ethyl acetate, melts at b. The starting material: 1-[p-(2-aminoethyl)-phenyl-sulphonyl]-2-imino-3-cyclopentyl-imidazolidinedihydrochloride is obtained according to the instructions given in Example 7(b).
EXAMPLE 29 39.7 g of 1-[p-(2-aminoethyl)-phenylsulphonyl]-2- imino-3-n-butyl-imidazolidine-dihydrochloride are dissolved in 100 ml of water, and the base is liberated with 150 ml of 2-n sodium hydroxide solution. The base is extracted with 3 times 250 ml of methylene chloride. To the methylene chloride solution (dried with sodium sulphate) are added 20 g of triethylamine. At room temperature is then added the solution of 15 g of 4- morpholinyl chloride in 100 ml of methylene chloride,
and stirring is maintained for 4 hours at room temperawith sodium sulphate, filtration, and concentration by evaporation, l-[p-(2-(4-morpholine carboxamido)- ethyl )-phenylsulphonyl ]-2-imino-3-n-butylimidazolidine which, recrystallized from ethyl acetate, melts at 176177.
The starting material: 1-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-n-butyl-imidazolidinedihydrochloride is obtained according to the instructions given in Example 1(b).
EXAMPLE 30 EXAMPLE 31 1,000 g of l-[p-(2( 3-butylureido)-ethy1)-pheny1 sulphonyl]-2-imino-3-cyc1ohexyl-imidazolidine are mixed with 500 g of lactose and 270 g of potato starch; the mixture is then moistened with an aqueous solution of 8.0 g of gelatine, and granulated through a sieve. After drying of the granulate, 60.0 g of potato starch 60.0 g of talcum, 10.0 g of magnesium stearate and illustrate the 20.0 g of colloidal silicon dioxide are mixed in; and the mixture is pressed into 10,000 tablets each weighing 200 mg and each containing mg of active substance. Optionally, the tablets may be provided with grooves for more precise adjustment of the dosage amount EXAMPLE 32 A granulate is prepared from 1,000 g of l-[p-(2-(3- buty1-thio-ureido)-ethyl)-phenyl-sulphonyl]-2-imino- 3-cyclohexyl-imidazolidine, 345.0 g of lactose and the aqueous solution of 6.0 g of gelatine. After drying, the granulate is mixed 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; the mixture is then pressed into 10,000 dragee cores. These are subsequently coated with a concentrated syrup made from 533.0 g of crystallized 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 dragees each weigh 240 mg and each contain 100 mg of active substance.
What is claimed is:
l. A compound of the formula 1,
R is alkyl of one to six carbon atoms, allyl, cycloalkyl of five to eight carbon atoms or cycloalkenyl of five to eight carbon atoms;
R is hydrogen, ethyl or methyl;
R is alkyl of one to six carbon atoms, cycloalkyl of at most eight carbon atoms, cycloalkenyl of at most eight carbon atoms, alkenyl of three to five carbon atoms or phenyl;
R is hydrogen, alkyl of one to six carbon atoms or phenyl; and
R and R together are a polymethylene chain of four to seven carbon atoms or morpholino;
X is oxygen or sulfur; and
m is 2 or 3; or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to claim 1, which is l-[p- 2-( 3-n-butyl-2-thioureido )-ethyl )-phenylsulfonyl ]-2 imino-3-n-butyl-imidazolidine.
3. A compound according to claim 1, which is l-[p- (2 3-n-butylureido )-ethyl)-phenylsulfonyl ]-2-imino- 3-cyclohexyl-imidazolidine.
v 4. A compound according to claim 1, which is l-[p- (2-( 3-n-butyl-2-thioureido )-ethyl )-phenylsulfonyl -2- imino-3-cyclohexyl-imidazolidine.
5. A compound according to claim 1, which is l-[p- 2-( 3-n-propylureido)-ethyl )-phenylsu]fonyl ]-2-imino- 3 4-methylcyclohexyl )-irnidazolidine.
6. A compound according to claim 1, which is l-[p- 2-( 3 -ethyl-2-thioureido )-ethyl )-phenylsulfonyl ]-2- imino-3-cyclopentylimidazolidine.

Claims (5)

  1. 2. A compound according to claim 1, which is 1-(p-(2-(3-n-butyl-2-thioureido)-ethyl)-phenylsulfonyl)-2-imino-3-n-butyl -imidazolidine.
  2. 3. A compound according to claim 1, which is 1-(p-(2-(3-n-butylureido)-ethyl)-phenylsulfonyl)-2-imino-3-cyclohexyl -imidazolidine.
  3. 4. A compound according to claim 1, which is 1-(p-(2-(3-n-butyl-2-thioureido)-ethyl)-phenylsulfonyl)-2-imino-3-cyclohexyl-imidazolidine.
  4. 5. A compound according to claim 1, which is 1-(p-(2-(3-n-propylureido)-ethyl)-phenylsulfonyl)-2-imino-3-(4 -methylcyclohexyl)-imidazolidine.
  5. 6. A compound according to claim 1, which is 1-(p-(2-(3-ethyl-2-thioureido)-ethyl)-phenylsulfonyl)-2-imino-3 -cyclopentylimidazolidine.
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GB1046174A (en) * 1964-04-20 1966-10-19 Bayer Ag Process for the production of n,n'-disulphonyl-1,3-diazacylco alkanes
US3538085A (en) * 1966-03-24 1970-11-03 Geigy Chem Corp 1-phenylsulfonyl-2-imino-imidazolidines and hexahydropyrimidines

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Publication number Priority date Publication date Assignee Title
GB1046174A (en) * 1964-04-20 1966-10-19 Bayer Ag Process for the production of n,n'-disulphonyl-1,3-diazacylco alkanes
US3538085A (en) * 1966-03-24 1970-11-03 Geigy Chem Corp 1-phenylsulfonyl-2-imino-imidazolidines and hexahydropyrimidines

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Title
Dietrich Chem. Abst. Vol. 70, No. 47450g (1969). QD1.A51 *
Dietrich Chem. Abst. Vol. 71, No. 91476q (1969). QD1.A51 *
Dietrich Chem. Abst. Vol. 72, No. 12728t (1970). QD1.A51 *
Dietrich Chem. Abst. Vol. 72, No. 31793b (1970). QD1.A51 *
Schotte et al. Chem. Abst. Col. 22, pages 1759 1760 (1928). QD1.A51 *
Yoshitomi Pharmaceutical Industries Chem. Abst. Vol. 62, column 16135 (1965) QD1.A51 *

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