Classifications

• • 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

Definitions

• the present invention relates to derivatives of l-[pcarbamoylethyhphenylsulfonyl1-2-imino imidazolidines, to pharmaceutical compositions containing these compounds and to the use thereof.
• 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
• R and R together are pentamethylene
• hypoglycemic action can be demonstrated in standard tests on experimental animals.
• 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,
• the substituent R as the alkyl group can be anyone of the alkyl groups listed under R having at most 4 carbon atoms.
• 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 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.
• 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.
• 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 fiirdorfe 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.
• a suitable aqueous-organic or organic solvent such as, e.g. methanol, ethanol, diethyl ether, chloroform or methylene chloride.
• 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.
• 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.
• 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.
• Such 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.
• the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby likewise stablisers can be added.
• 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.
• 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.
• sulphonyl-hydrocinnamamide is obtained: 1- [p-[2-(ethylcarbamoyl)-ethyl] phenylsulphonyl] 2 imino-3-(2- methylcyclohexyl)-imidazolidine, M.P. 165-167 from acetone;
• N-propyl-hydrocinnamamide M.P. 52-54
• 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.
• N-methyl-hydrocinnamamide M.P. 59-60
• N-isobutyl-hydrocinnamamide M.P. 58-61- is obtained: N-isobutyl-p-ch1orosulphonyl-hydrocinnamamide, which is further used, as oil, in the crude state;
• N-n-butyl-hydrocinnamamide M.P. 25
• N-n-butyl-p-chlorosulphonyl-hydrocinnamamide which is further used, as oil, in the crude state
• N-ethyl-hydrocinnamamide M.P. 58-60
• N-ethyl-p-chlorosulphonyl-hydrocinnamamide which is further used, as oil, in the crude state.
• N-substituted chlorosulfonyl-hydrocinnamamides used as starting materials can be obtained analogously to Example 1(b).
• a compound according to claim 1 which is 1-[p-[2- (propylcarbamoyl)-ethyl]-phenylsulfonyl] 2 imino-3- sec.butyl-imidazolidine.
• a compound according to claim 1 which is, 1-[p-[2- (n-butylcarbamoyl)-ethyl]-phenylsulfonyl] 2 imino-3- cyclopentyl-imidazolidine.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Other In-Based Heterocyclic Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=4392081

Family Applications (1)

Country Status (8)

Cited By (2)

• 0
  • BE BE755683D patent/BE755683A/fr unknown
• 1970
  • 1970-08-27 NL NL7012725A patent/NL7012725A/xx unknown
  • 1970-09-01 US US00068795A patent/US3712905A/en not_active Expired - Lifetime
  • 1970-09-03 IL IL35227A patent/IL35227A0/xx unknown
  • 1970-09-03 ZA ZA706036A patent/ZA706036B/xx unknown
  • 1970-09-03 DE DE19702043800 patent/DE2043800A1/de active Pending
  • 1970-09-03 ES ES383342A patent/ES383342A1/es not_active Expired
  • 1970-09-03 FR FR7032045A patent/FR2070669A1/fr not_active Withdrawn

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