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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids

Definitions

• the present invention relates to derivatives of 1- [paminoalkyl) -phenylsulfonyl] -2-imino-imidazolidines, to pharmaceutical compositions containing these compounds and to the use thereof.
• the present invention relates to compounds of formula wherein R is alkyl having from one to six carbon atoms, alkenyl having from three to five carbon atoms, cycloalkyl or cycloalkenyl having from five to eight carbon atoms, or phenylalkyl having at most nine carbon atoms;
• R is hydrogen, methyl or ethyl
• R is alkyl having from one to six carbon atoms
• n is the integer 2 or 3;
• n is the integer 1, 2, 3, or 4;
• y is oxygen or sulfur
• Z is oxygen, sulfur, or a sulfoxide or sulfone grouping
• hypoglycemic action can be demonstrated in standard tests on experimental animals.
• R as alkyl can be the methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert. butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, l-methylbutyl, l-ethylpropyl or the 1,2-dimethylpropyl group, or a straight-chained or branched hexyl radical, e.g. an n-hexyl radical, e.g.
• R can be the allyl, l-methylallyl, Z-methylallyl, the 2- or 3-butenyl or the 2-, 3- or 4-pentenyl group.
• R can be the cyclopentyl group which may be optionally substituted by alkyl radicals having one to three carbon atoms, the cyclohexyl group which may be substituted by ethyl or methyl, and the cycloheptyl group optionally sub- 3,729,462 Patented Apr.
• R can be the 2-cyclopenten-1-yl, the 2-cyclohexen-l-yl, the 3-cyclohexene-1-yl, the 2-methyl-2-cyclohexen-l-yl, the 3-cyclohepten-1-yl group, or a cyclooctenyl group.
• phenylalkyl R can be the benzyl, the phenylethyl or the a-methylphenylethyl group.
• R embraces the same alkyl groups as those given under R Using the process according to the invention, compounds of Formula I are produced by reacting an amine of formula I IH wherein R R and m have the meanings given under Formula I, with a carboxylic acid or thiocarboxylic acid of formula wherein R, Z, n and Y have the meanings given under Formula I,
• the reaction of an amine of Formula II with a carboxylic acid or thiocarboxylic acid of Formula III can be performed, e.g. by first converting the amine into the ammonium salt of an acid corresponding to Formula 111; and then converting the ammonium salt, by dry heating, into the amide of Formula I.
• an amine of Formula II is reacted with a carboxylic acid or thiocarboxylic acid of Formula III in the presence of a water-splitting agent in an inert solvent.
• a particularly suitable water-splitting agent is, e.g. N,N'-dicyclohexylcarbodiimide.
• Suitable inert solvents are, e.g. hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, chloroform, tn'chloroethylene and lower ketones such as acetone or methyl ethyl ketone.
• Suitable reactive derivatives of a carboxylic acid or thiocarboxylic acid of Formula HI are, e.g. halides, especially chlorides, lower alkyl esters, especially methyl or ethyl ester, phenyl ester, amides, lower monoor dialkylamides, especially N-methylarnides and N,N-dimethylamides, diphenylamides, also N-acylamides such as, e.g. acetylamides. and benzoylamides.
• reaction of the aforementioned reactive derivatives of carboxylic or thiocarboxylic acids is performed, e.g. at room temperature, or by heating, in one of the above already mentioned organic solvents.
• the reaction may be carried out without the addition of condensation agents; optionally, however, such agents, e.g. alkali metal alcoholates and alkali metal hydroxides, can be added.
• a halide of a carboxylic acid or thiocarboxylic acid of Formula HI is reacted according to the invention prefer ably in the presence of an acid-binding agent.
• acidbinding agents 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-as sodium hydroxide, sodium acetate, sodium hydrogen carbonate, sodium carbonate and sodium phosphate, or the corresponding potassium compounds. It is also possible to use calcium oxide, calcium carbonate, as well as calcium phosphate and magnesium carbonate. Also suitable, in place of inorganic bases or salts, are organic bases such as, e.g. pyridine, trimethylamine or triethylamine, diisopropylamine, or collidine. Added in excess, these can also be used as solvent.
• N-alkali metal derivatives of these compounds such as, e.g. sodium, potassium or lithium derivatives.
• the starting compounds of Formula II can be produced by one of several processes as described in Belgian Pat. 729,837.
• one of these processes comprises adding a solution of a halide or the anhydride of a sulphonic acid of Formula IV:
• R and m have the meaning given in Formula I, in an inert solvent, especially a solution of the chloride in acetone to a 2-amino-2-imidazoline derivative of Formula V:
• N H (V) wherein R and R have the meanings given under Formula I; in the presence of an acid binding agent, such as an aqueous alkali metal hydroxide solution, and then heating the mixture for a short time, and subsequently hydrolytically splitting off the protective acyl group (RCO-), e.g. by refluxing the N- acyl compound obtained as intermediate product with 2 N hydrochloric acid for about 6 hours.
• an acid binding agent such as an aqueous alkali metal hydroxide solution
• Suitable reactive derivatives of the sulphonic acids of Formula IV are halides, especially chlorides and anhydrides of Formula IVa:
• the carboxylic acids of Formula III (obtained with thiolates of Formula VI), in which Z represents a sulphur atom, can be converted by oxidation, e.g. with hydrogen peroxide or with potassium permanganate, into the corresponding carboxylic acids of Formula III, wherein Z represents the sulphoxide or sulphone grouping.
• starting materials of Formula II are obtained by reacting substituted p-(aminoalkyl)- benzenesulfonamides of formula wherein m has the meaning given under Formula I, with substituted N-(Z-bromoalkyl)-cyanamides in alkaline medium.
• the new substances, or the pharmaceutically acceptable salts thereof can be administered orally or parenterally.
• suitable inorganic or organic acids such as, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, lactic acid, succinic acid, tartaric acid and maleic acid, but also hypoglycemically active 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.
• 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 and tablets contain preferably 10-200 mg. of an active substance according to the invention, whereby the content of active substance is 20- by weight.
• the tablets and drages are produced by combining the active substance, e.g.
• solid pulverulent carriers such as lactose, saccharose, sorbitol or 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.
• Tablets and drage cores are coated, e.g. with concentrated sugar solutions which may 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. for identification of the various dosages of active substance.
• suitable dosage units for oral administration are hard gelatine 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 stabilisers can be addedd.
• a granulate is produced from 1000 g. of l-[p-(2- ethoxyacetamidoethyl) phenylsulphonyl] 2 imino-3- cyclohexyl-imidazolidine, 345 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 the mixture is pressed into 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 533.0 g.
• Example 1 To a solution of 35.6 g. of 1- [p-(Z-aminoethyl)-phenylsulphonyl] 2-imino-3-methylimidazolidine dihydrochloride, M.'P. 230-235 in 100 ml. of water are added 150 ml. of 2-n sodium hydroxide solution; and the liberated base is extracted With methylene chloride. To the extract, dried with sodium sulphate, are added at 20.6 g. of N,N-dicyclohexylcarbodiimide. To the whole is then added dropwise at 0, over minutes, a solution of 9.0 g. of methoxyacetic acid in 30 ml. of methylene chloride.
• Example 2 To a solution of 42.3 g. of 1-[p-(2-aminoethyl)-phenylsulphonyl] 2 imino-3-cyclohexyl-imidazolidine dihydrochloride, M.P. 247-250, in 200 ml. of water are added "300 ml. of 2-n sodium hydroxide solution, and the whole is extracted with methylene chloride. To the extract dried with sodium sulphate are added 50.5 g. of triethylamine. An addition is then made dropwise at room temperature, Within 20 minutes, of a solution of 13.5 g. of ethoxyacetyl chloride in ml.
• reaction solution is then Washed first with 100 ml. of 2-n sodium hydroxide solution, and afterwards twice with 100 ml. of Water.
• the combined aqueous phases are extracted twice with methylene chloride, and the obtained methylene chloride extracts combined with the washed reaction solution.
• Example 4 An amount of 43.7 g. of 1-[p-(2-aminoethyl)-phenylsulphonyl] 2 imino-3-(4-methylcyclohexyl)-imidazolidine dihydrochloride, M.P. 260, is suspended, with stirring, in a mixture of 500 ml. of methylene chloride and 100 ml. of a 50% aqueous potassium hydroxide solution, and stirring then proceeds for a further 30 minutes. To the suspension, whilst it is being cooled with ice, is then added dropwise a solution of 15 .0 g. of 2-methylmercaptopropionic acid chloride in 100 ml. of methylene chloride; stirring is continued for a further 30 minutes.
• the organic phase is separated, washed with water, and the methylene chloride evaporated oil.
• the residue is dissolved in ethyl acetate, and the solution repeatedly extracted. with 2-n hydrochloric acid.
• the combined acid extracts are made alkaline, whilst being cooled with ice, with conc. aqueous sodium hydroxide solution.
• the precipitated crude product is taken up with methylene chloride, the methylene chloride solution dried with sodium sulphate, and concentrated by evaporation.
• Example 5 An amount of 41.5 g. of 1-[p-(Z-aminoethyD-phenylsulphonyl] 2 imino-3-isobutyl-imidazolidine dihydrochloride monohydrate, M.P. 151-152", is suspended, with stirring, in a mixture of 500 ml. of methylene chloride and 100 ml. of 50% aqueous potassium hydroxide solution; stirring proceeds for a further 30 minutes. To the suspension, cooled with ice, is then added dropwise a solution of 17.0 g. of 3-ethylmercaptopropionic acid chloride in 100 ml. of methylene chloride; stirring continues for a further 30 minutes.
• Example 7 To a solution of 37.1 g. of 1-[p-(2-aminoethyl)phenylsulphonyl]-2-imino-3 ethyl-imidazolidine dihydrochloride, M.P. 242244, in ml. of water are added ml. of 2-n sodium hydroxide solution, and the base is taken up with methylene chloride. The methylene chloride solution (dried with sodium sulphate) is concen trated by evaporation to dryness, and the residue dissolved in 300 ml. of tetrahydrofuran. To this soluiton are added portionwise, at room temperature, 3 6.0 g.
• Example 8 To a solution of 41.0 g. of 1-[p-(2-aminoethyl)-phenylsulphonyl] 2 imino-3-cyclopentyl-imidazolidine dihydrochloride, M.P. 270, in 100 ml. of water are added 150 ml. of 2-n sodium hydroxide solution; and the base is taken with methylene chloride. The methylene chloride solution is dried with sodium sulphate, the methylene chloride distilled off, and the l-[p-(2-aminoethyl)-phenylsulphonyl]-2-imino-3-cyclopentyl-imidazolidine remaining behind dissolved in 300 ml. of dioxane.
• Example 9 The base, liberated from a solution of 41.0 g. of l-[p- (Z-aminoethyl)phenylsulphonyl] 2-imino-3-cyclopentylimidazolidine dihydrochloride, M.P. 270, in 200 ml. of water by the addition of 300 ml. of 2-n sodium hydroxide solution, is taken up with methylene chloride; the methylene chloride solution is then dried with sodium sulphate, and the methylene chloride distilled ofi.
• the methoxydithioacetic acid benzyl ester used as starting material can be obtained according to the following prescription:
• Example 10 Analogously to Example 1, with the use, each time, of 20.6 g. of N,N'-dicyclohexyl-carbodiimide, are obtained:
• a compound of formula R is alkyl of from one to six carbon atoms; alkenyl of from three to five carbon atoms; cycloalkyl, cycloalkenyl, alkyl substituted cycloalkyl or alkyl substituted cycloalkenyl of from five to eight carbon atoms; or phenylalkyl of at most three carbon atoms in the alkyl chain;
• R is hydrogen, methyl or ethyl
• R is alkyl of from one to six carbon atoms
• n is the integer 2 or 3;
• n is the integer 1, 2, 3 or 4;
• Y is oxygen or sulfur
• Z is oxygen, sulfur or a sulfoxide or sulfone grouping

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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)

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Cited By (1)

• 0
  • BE BE755685D patent/BE755685A/xx unknown
• 1969
  • 1969-09-04 CH CH74872A patent/CH518945A/de not_active IP Right Cessation
  • 1969-09-04 CH CH1340069A patent/CH519501A/de not_active IP Right Cessation
• 1970
  • 1970-08-27 FI FI702364A patent/FI52573C/fi active
  • 1970-08-27 DK DK440870A patent/DK131674C/da active
  • 1970-08-27 NO NO03276/70A patent/NO128997B/no unknown
  • 1970-08-27 SE SE11648/70A patent/SE367824B/xx unknown
  • 1970-08-27 NL NL7012732.A patent/NL165155C/xx not_active IP Right Cessation
  • 1970-09-01 US US00068793A patent/US3729462A/en not_active Expired - Lifetime
  • 1970-09-03 CA CA092253A patent/CA920601A/en not_active Expired
  • 1970-09-03 ES ES383344A patent/ES383344A1/es not_active Expired
  • 1970-09-03 GB GB4210670A patent/GB1306602A/en not_active Expired
  • 1970-09-03 ZA ZA706044A patent/ZA706044B/xx unknown
  • 1970-09-03 BG BG015600A patent/BG17962A3/xx unknown
  • 1970-09-03 CS CS6050A patent/CS166015B2/cs unknown
  • 1970-09-03 AT AT802270A patent/AT294824B/de not_active IP Right Cessation
  • 1970-09-03 FR FR7032047A patent/FR2070671B1/fr not_active Expired
  • 1970-09-03 IL IL35224A patent/IL35224A/en unknown
  • 1970-09-03 SU SU1471571A patent/SU398039A3/ru active
  • 1970-09-03 PL PL1970142967A patent/PL73403B1/pl unknown
  • 1970-09-03 DE DE2043773A patent/DE2043773C3/de not_active Expired
  • 1970-09-03 IE IE1148/70A patent/IE34504B1/xx unknown

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