US3812144A - Derivatives of p-aminoalkylbenzene sulfonamide - Google Patents

Derivatives of p-aminoalkylbenzene sulfonamide Download PDF

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US3812144A
US3812144A US00805843A US80584369A US3812144A US 3812144 A US3812144 A US 3812144A US 00805843 A US00805843 A US 00805843A US 80584369 A US80584369 A US 80584369A US 3812144 A US3812144 A US 3812144A
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ethyl
imino
phenylsulfonyl
imidazolidine
butyl
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H Dietrich
C Lehmann
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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

Definitions

  • the present invention relates to new derivatives of paminoalkylbenzene sulfonamide, processes for their preparation, medicaments containing the new compounds and their use.
  • R is an alkyl group with not more than 12 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkyl or cycloalkenyl group with not more than 7 carbon atoms or a phenylalkyl group with not more than 9 carbon atoms,
  • R is hydrogen or an alkyl group with not more than 2 carbon atoms
  • R is hydrogen, an alkyl group or chloroalkyl group with not more than 7 carbon atoms, an alkenyl group with not more than 5 carbon atoms, a cycloalkyl or cycloalkenyl group with not more than 8 carbon atoms, a phenyl group or a phenylalkyl or phenylalkenyl group with not more than 10 carbon atoms, wherein the phenyl group can be monoto tri-substituted by halogen of atomic number 35, trifluoromethyl groups, alkyl groups with not more than 4 carbon atoms, hydroxyl groups, alkoxy or alkylthio groups with not more than 12 carbon atoms, and
  • R is hydrogen or the methyl group, and their pharmaceutically acceptable acid addition salts.
  • the new compounds of the invention have been found to have hypoglycemic activities which are illustratively demonstrated in rats by orally administering the test compound to groups of 5 to 6 animals which have not been fed for 24 hours. Blood samples are taken from a vein of the animal and the blood sugar content is determined according to the method of Hagedorn-Jenson with an auto analyzer.
  • butyl-imidazolidine 1- [p- Z-propionamido-ethyl) -phenylsulfonyl] -2-imino-3- sec.butyl-imidazolidine, 1- [p-(2-butyramido-ethy1 -pheny1su1fonyl] -2-imino-3- sec. butyl-imid azolidine, 1- [p- (Z-butyramido-ethyl) -phenylsu1fonyl] -2-imino-3-tert.
  • butyl-imidazolidine 1- [p- Z-isovaleramido-ethyl) -phenylsulfony1] -2-imino-3- tert. butyl-imidazolidine, 1- [p Z-butyramido-ethyl-phenylsulfonyl] -2-imino-3- cyclo-pentyl-imidazolidine, 1- [p- 2-valeramido-ethyl) -pheny1sulfonyl] -2-imino-3- cyclo-pentyl-imidazolidine, 1- [p- (2-cyclohexane-carboXamido-ethyl) -phenylsulfonyl]- 2-imino-3 -cyclopentyl-imidazolidine, 1- p- 2-formamido-ethyl) -phenylsulfonyl] -2-imino-3
  • the toxicity of the compounds of the invention on oral administration as demonstrated in rats is of favorable low order. These properties render the compounds of the invention suitable for the treatment of diabetes.
  • R can have the following meaning:
  • the substituent R as alkyl group can be the methyl or ethyl group and the substituent R as alkyl group can be the alkyl groups named under R with not more than 7 carbon atoms;
  • chloroalkyl groups the l-chloroethyl, l-chloropropyl,
  • cycloalkyl group the cyclopropyl, cyclopropylmethyl
  • cyclobutyl cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, methylcyclohexyl, 4-methylcyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, cycloheptylmethyl, or the cyclooctyl group;
  • cycoalkenyl groups the 2-cyclopenten-l-yl, 2-cyclohexenl-yl, 3-cyclohexen-1-yl, 1-methyl-3-cyclohexen-lyl, 2-methyl-2-cyclohexen-1-yl, 3-methyl-2-cyclohexenl-yl, 2-cyclohepten-1-yl, 3-cyclohepten-1-yl, 2 cycloocten-l-yl or the 3-cycloocten-l-yl group;
  • phenylalkyl or phenylalkenyl groups the benzyl, phenethyl, phenylpropyl, phenylbutyl or the styryl group.
  • the phenyl group appearing in the definition of R may be monoto tri-substituted.
  • halogen chlorine, fluorine or bromine
  • lower alkyl groups the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl or the tertbutyl group; and,
  • alkoxy or alkylthio groups the methoxy, ethoxy, methylthio or the ethylthio group.
  • compounds of general formula I are prepared by reaction of a reactive functional derivative of a sulfonic acid of general formula II R4 (11) in which m, R and R have the meaning given under formula I with a compound of general formula III H-N N-Rl b t-H in which R and R have the meaning given under formula I and, if desired, the reaction product can be converted with an inorganic or organic acid into an addition salt.
  • reactive functional derivative of a sulfonic acid of general formula II are suitable, e.g. a halogenide, particularly a chloride, or also an anhydride of general formula Ha in which m, R and R have the meaning given under formula I.
  • the reaction is preferably carried out in the presence of an inert organic solvent, which is miscible or inmiscible with water, in the presence or the absence of water.
  • Suitable inert organic solvents are hydrocarbons, such as benzene, toluene or xylene, ether-like solvents such as ether, dioxane or tetrahydrofurane, chlorinated hydrocarbons such as rnethylenechloride and lower ketones such as acetone or rnethylethylketone. It is preferable to add an acid binding agent to the reaction solution.
  • suitable inorganic bases or salts e.g.
  • alkalimetal hydroxides alkalimetal hydrogencarbonates, alkalimetal carbonates or alkalimetal phosphates, such as the corresponding sodium or potassium compounds.
  • organic bases such as pyridine, trimethyl or triethylamine, N,N diisopropyl-ethylamine or collidine which are added in excess or which can also be used as solvent.
  • Starting materials of general formula II are compounds in which m, R and R are as defined under formula I.
  • One group of sulfonylchlorides of the formula II, wherein R is a lower alkyl group can be prepared by reaction of lower aliphatic carboxamides, which are substituted on the nitrogen atom by the phenylethyl or by the phenylpropyl group, with chlorosulfonic acid.
  • a second group of sulfonyl chlorides of general formula II, wherein R is an optionally substituted phenyl group may be prepared by reacting an optionally substituted benzoylchloride with p-nitro-phenethylamine or with p-nitrophenyl-propylamines to obtain the corresponding -N-(p nitro-phenethyl)- and N-(p-nitro-phenylpropyl)-benzam ides respectively. These nitro compounds are reduced with iron powder in hydrochloric acid tothe corresponding N- (p-amino-phenylethyl)- and N-(p-amino-phenylpropyl)- benzamides respectively. The reaction products are finally diazotised with sodium nitrite in hydrochloric acid and the diazonium salt solution is added to a solution of cupric chloride in water and glacial acetic acid which is saturated with sulfur dioxide.
  • compounds of general formula I are prepared by the reaction of an acid of general formula IV R, cooH V) in which R has the meaning given under formula I or a reactive functional derivative of such an acid with a compound of general formula V in which m, R R and 'R have the meaning given under formula I and, if desired, the compound obtained is converted with an inorganic or organic acid into an addition salt.
  • the acylation and benzoylation respectively of compound V is carried out in a known manner, e.g. by reaction of the corresponding acid halogenides, -anhydrides or mixed-anhydrides, preferably in the presence of an acid binding or water binding agent or by treatment with reactive acid esters.
  • the reaction is preferably carried out in the presence of an inert organic solvent.
  • Suitable inert organic solvents are hydrocarbons such as benzene, toluene or xylene, ether-like solvents such as ether, dioxane or tetrahvdrofurane, chlorinated hydrocarbons such as methylenechloride and lower ketones, such as acetone or methylethylketone.
  • an acid binding agent such as inorganic bases or salts, e.g. alkalimetal hydroxides, alkalimetal hydrogencarbonates, alkalimetal carbonates or alkalimetal phosphates, such as the corresponding sodium or potassium compounds.
  • organic bases such as pyridine, trimethylor triethylamine, N,N-diisopropylethylamine or collidine which can be used as solvent if added in excess.
  • an acid of general formula IV is reacted with a compound of general formula V in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as tetrahydrofuran.
  • a carbodiimide such as dicyclohexylcarbodiimide
  • an inert solvent such as tetrahydrofuran.
  • Lower alkyl esters, e.g. the methyl ester or the ethyl ester of the acids of general formula IV yield on heating with compounds of general formula V, the corresponding substituted amides of general formula I.
  • An alternative form of the method for the preparation of a halogenide or anhydride, in particular a mixed anhydride, is to react a carbonic acid half ester with a compound of general formula V, preferably in the presence of an acid binding agent, e.g. a strong tert. organic base like triethylamine, pyridine or s-collidine, which, if added in excess, can also serve as the reaction medium.
  • an acid binding agent e.g. a strong tert. organic base like triethylamine, pyridine or s-collidine, which, if added in excess, can also serve as the reaction medium.
  • Reactive esters of acids of general .formula IV are the p-nitro-phenylester and the cyanomethylester.
  • compounds of general formula I are prepared by condensation of compounds of general formula VII H,Rz H6:CH m-omwwnmQ-sm-h 1-12,
  • R is hydrogen, an arylmethyl, diarylmethyl or a triarylmethyl group, the methyl or the allyl group, with a reactive cyanic acid derivative under ring closure and optionally under cleavage of a R halogenide and, if desired, the compound obtained is converted with an inorganic or organic acid into an addition salt.
  • R is preferably the benzyl, benzhydryl or the trityl group.
  • cyanogenhalides such as cyanogenchloride or cyanogenbromide or cyanic acid esters, particularly cyanic acid phenyl esters.
  • the reaction is preferably carried out in the presence of an inert organic solvent which is miscible or immiscible with water, in the presence or absence of Water.
  • Suitable inert organic solvents are hydrocarbons such as benzene, toluene or xylene; lower alkanols, such as methanol or ethanol; ether-like solvents such as ether, dioxane or tetrahydrofuran; chlorinated hydrocarbons such as methylenechloride; lower ketones, such as acetone or methylethylketone; carbonic acid esters such as ethyl acetate; carbonic acid nitriles such as acetonitrile; or sulfones, such as tetrahydrothiophene-1,l-dioxide.
  • the reaction can be carried out in the presence or absence of an acid binding agent.
  • acid binding agents there are suitable inorganic bases or salts such as alkalimetal hydroxides, alkalimetal hydrogen carbonates, alkalimetal carbonates or alkalimetal phosphates, e.g. the corresponding sodium or potassium compounds. Additionally, there can also be used calcium carbonate, calcium phosphate and magnesium carbonate.
  • compounds of general formula I are prepared by condensing a compound of general formula VIII 4 (VIII) in which m, R and K, have the same meaning as defined under formula I, with a reactive ester of a hydroxy compound of general formula IX in which R and R have the same meaning given under formula I under ring closure and, if desired, the compound obtained is converted with inorganic or organic acid into an addition salt.
  • Suitable reactive esters of hydroxy compounds of general formula IX are, e.g. halogenides, particularly chlorides or bromides, additional sulfonic acid esters, e.g. the 0- or p-toluene sulfonic acid ester or the methane sulfonic acid ester.
  • the condensation is preferably carried out in an solvent which is miscible or immiscible with water, in the presence or absence of water.
  • solvents there can be used alkanols, e.g. butanol; ether-like solvents e.g. dioxane; diethyleneglycolmonomethyl ether, carbonic acid amides such as N,N-dimethylformamide' or sulfoxides, such as dimethylsulfoxide. It is preferable to carry out the condensation in the presence of an acid binding agent.
  • compounds which are named after the third method for preparation also there can be used tert.organic bases such as, e.g. N,N-diisopropylethylamine.
  • a group of bromides of general formula IX may be prepared if a l-alkyl-a ziridine [see A. Weissberger, Heterocyclic Compounds with Three and Four-Membered Rings, Part One, John Wiley Sons Inc., London (1964)] is reacted with cyanogen bromide in dioxane.
  • compounds of general formula I are prepared by condensation and cyclization of a reactive ester of a compound of general formula X.
  • Suitable reactive esters of a hydroxy compound of general formula X are, e.g. halogenides, particularly chlorides or bromides, or sulfonic acid esters, particularly a benzene sulfonic acid ester which is substituted in paraposition by the amidoalkyl group
  • the condensation is preferably done in a solvent.
  • halogenides particularly chlorides or bromides
  • sulfonic acid esters particularly a benzene sulfonic acid ester which is substituted in paraposition by the amidoalkyl group
  • the reaction is preferably carried out in the presence of an acid binding agent.
  • an acid binding agent there is most suitable an excess of bases of general formula XI.
  • a group of such compounds can be prepared in the following way.
  • compounds of general formula I in which R is only hydrogen are prepared by formylation of compounds of general formula XII Ba ba H (XII) in which m, R R and "R have the same meaning given under formula I with chloral and, if desired, the compounds obtained can be converted with an inorganic or organic acid into an addition salt.
  • the formylation is done according to Collinse, Am. Soc. 74, 3933 (1952) in an inert solvent, e.g. in dioxane, tetrahydrofuran, benzene, toluene or chlorinated hydrocarbons e.g. methylenechloride.
  • the compounds of general formula I which are prepared according to the inventive method for preparation are converted if desired into the salts with inorganic or organic acids.
  • the preparation of these salts can be done by reaction of compounds of general formula I with an equivalent amount of acid in a suitable aqueous-organic or inorganic solvent like methanol, ethanol, diethylether, chloroform or methylenechloride.
  • Suitable addition salts are salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethanesulfonic acid, p-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, hydroxysuccinic acid, tartaric acid, citric acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid, addition salts with blood sugar depressing sulfonyl ureas e.g.
  • the new compounds are preferably administered orally.
  • the daily doses are between 30 and 300 mg. for adult patients with normal weight.
  • Suitable dosage forms like drages and tablets, contain preferably 30 to 300 mg. of a compound of the invention, i.e. 20 to of a compound of general formula I, or a pharmaceutically acceptable acid addition salt thereof.
  • the active compound is combined, e.g. with a solid powdery carrier like lactose, saccharose, sorbitol, mannitol, starch, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, if desired under addition of sliding agents like magnesium or calcium stearate or polyethylene glycols to form tablets or drages cores.
  • a solid powdery carrier like lactose, saccharose, sorbitol, mannitol, starch, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder
  • cellulose derivatives or gelatine if desired under addition of sliding agents like magnesium or calcium stearate or polyethylene glycols to form tablets or drages cores.
  • the last-named are coated with concentrated solutions of sugar which may also contain some arabic gum, talc or titan dioxide or with a volatile organic solvent or mixtures of solvents which contain dissolved lacquer. It is possible to add to these coatings pigments to mark different doses of the active ingredients.
  • plugged capsules contain the active ingredient preferably as granulate e.g. in mixture with fillers like corn starch and/or sliding agents like talc or magnesium stearate and, if desired, stabilizers like sodium meta-bisulphite (Na S O or ascorbic acid.
  • the active ingredient is preferably dissolved or suspended in suitable solvents like liquid polyethyleneglycols whereby if desired Stabilizers can be added.
  • gummi arabicum 250 g. talc, 20 g. colloidal silicon dioxide and 20.5 g. 1-cyclohexyl-Z-imino-imidazolidine-hydrochloride and 30.4 g. p-(Z-valeramido-ethyl))-benzenesulfonylchloride the 1-[p-(2-valeramido-ethyl)-phenylsulfonyl] Z-imino-3-cyclohexyl-imidazolidine, H O, M.P. 154- 155;
  • chlorosulfonic acid the p-(2-isovaleramido-ethyl)-benzenesulfonylchloride
  • Example 2 (a) According Example 1 (a J one obtains from 17.8 g. l-butyl-2-imino-imidazolidine-hydrochlorine in sodium hydroxide and 35.8 g. p-[2-(o-chlorobenzamido)-ethyl]- benzenesulfonylchloride the 1 ⁇ p [2 (o-chlorobenzamido) ethyl] phenylsulfonyl] 2 imino-3-butyl-- imidazolidine, M.P. 1551S7 (from isopropanol).
  • the sulfonyl chloride used as starting material is prepared according the following procedure:
  • Example 3 13 phenylsulfonyl1-2-imino 3-tert.butyl-imidazolidine, M.P. 152-154 (from ethanol).
  • Example 4 (a) According Example 1 (a) one obtains from 17.8 g. 1-butyl-2-imino-imidazolidine-hydrochloride in sodium hydroxide and 35.4 g. p-[2-(o-methoxy-benzamido)- ethyl]-benzenesulfonylchloride the l- ⁇ -p-[2-o-methoxymethoxy-benzamido)-ethyl]-phenylsulfonyl ⁇ -2-imino 3- butyl-imidazolidine, M.P. 145-l46 (from methanol).
  • the sulfonylchloride used as starting material is prepared according to the following method:
  • Example 2 (b) According Example 2 (b-d) one obtains starting with 17.1 g. o-methoxy-benzoylchloride with 20.3 g. pnitro phenethyl amine the N-(p-nitro-phenethyl))-omethoxy-benzamide of M.P. 149-150 (from acetic acid ethylester); 30.0 g. of this nitro compound are reduced with 16.0 g. iron powder to yield the N-(p-arninophenethyl)-o-methoxy-benzamide-hydrochloride of M.P. 211-214 (from methanol) of which are 30.5 g. diazotized in conc. hydrochloride acid with 7.6 g.
  • the diazonium salt solution yields with a solution of cupric chloride in water and glacial acetic acid which is saturated with sulfodioxide the p-[2-(o-methoxybenzamido)-ethyl]-benzenesulfonylchloride which melts at 140-143 (crude products).
  • Example 5 (21) According Example 1 (a) one obtains from 16.4 g. 1 propyl 2 imino imidazolidine-hydrochloride in sodium hydroxide and 35.4 g. p-[Z-(m-methoxy-benzamido)-ethyl]-benzenesulfonylchloride the 1- ⁇ p-[2-(mmethoxy-benzamido)-ethyl]-phenylsulfonyl ⁇ 2 imino-3- propyl imidazolidine, M.P. 144-147 (from ethyl acetate).
  • the sulfonylchloride used as starting material is prepared according the following procedure:
  • Example 2 (b) According Example 2 (b-d) one obtains starting with 17.1 g. m-methoxy-benzoylchloride with 20.3 g. pnitro-phenethylamine the N-(p-nitro-phenethyD-m-methoxy-benzamide M.P. 151-152 (from ethyl acetate); 30.0 g. of this nitro compound are reduced with 16.0 g. iron powder to yield the N-(p-amino-phenethyl)-n-methoxybenzamide-hydrochloride, M.P. 205-209 of which 30.5 g. are diazotized in concentrated hydrochloric acid with 7.6 g.
  • the diazonium salt solution yields with a solution of cupric chloride in water and glacial acetic acid which is saturated with sulfurdioxide the p-[Z- (m methoxy-benzamido)-ethyl]-benzenesulfonylchloride (crude product).
  • Example 6 According Example 1 (a) one obtains from 17.8 g. 1- butyl 2 imine-imidazolidine-hydrochloride in sodium hydroxide and 35.4 g. p-[2-(m-methoxy-benzamido)- ethyl] benzenesulfonylchloride the l- ⁇ p-[2-'(m-methoxybenzamido) ethyl] phenylsulfonyl ⁇ 2 imino-3-butylimidazolidine, M.P. 137-141 (from methanol).
  • Example 7 According Example 1 (a) one obtains from 17.8 g. 1- tert.butyl 2 imino imidazolidine-hydrochloride in sodium hydroxide and 35.4 g. p-[Z-(m-methoxy-benzamido) ethyl]-benzenesulfonylchloride the l- ⁇ p-[2-(mmethoxy benzamido) ethyl]-phenylsulfonyl ⁇ -2-imino 3-tert.-butyl-imidazolidine of M.P. 134-136 (from ethyl acetate).
  • Example 8 (a) According Example 1 (a) one obtains from 17.8 g. 1tert.butyl-2-imino imidazolidine hydrochloride in sodium hydroxide and 33. 8 g. p-[2-(o-toluamido)-ethyl]- benzenesulfonylchloride the l- ⁇ p[2-(o-toluamido)-ethyl]- phenylsulfonyl ⁇ 2 imino 3 tert.butyl-imidazolidine of M.P. 160-161.
  • the sulfonylchloride used as starting material is prepared according to the following procedure:
  • Example 2 (b) According Example 2 (b-d) one obtains starting with 15.5 g. o-toluoylchloride with 20.3 g. p-nitro-phenethylamine the N-(p-nitro phenethyl) p toluamide (crude products); 28.4 g. of this nitro compound are reduced with 16.0 g. iron powder to yield the N-(p-aminophenethyl) o-toluamide-hydrochloride (crude product) of which 28.4 g. are diazotized in conc. hydrochloride acid with 7.6 g.
  • the diazonium salt solution yields with a solution of cupric chloride in water and glacial acetic acid which is saturated with sulfurdioxide the p [2-(o-toluamido)-ethyl]-benbenesulfonylchloride (crude product).
  • Example 9 (a) According Example 1(a) one obtains from 13.6 g. l-methyl-2-imino-imidazolidinerhydrochloride in sodium hydroxide and 39.0 g. p-EZ-(Z-methoxy-S-chlorobenzamido)-ethyl]-benzenesulfonylchloride the 1- ⁇ p-[2- (Z-methoxy 5 chloro-benzamido)-ethyl]-phenylsu]fonyl ⁇ -2-irnino-3-methyl-imidazolidine of M.P. 140-14l (from ethyl acetate).
  • the sulfonylchloride used as starting material is prepared according to the following procedure:
  • Example 2(b-d) one obtains starting with 20.6 g. 2-m'ethoxy-S-chlorobenzoylchloride with 20.3 g. p-nitro-phenethylamine the N-(p-nitrdphenethyD-Z- methoxy-S-chloro-benzamide, M.P. 158-160"; 30.0 g. of this nitro compound are reduced with 16.0 g. iron powder to yield the N-(p-amino-phenethyl)-2-methoxy-5-chlorobenzamide-hydrochloride (crude product) of which 34.0 g. are diazotized in conc. hydrochloride acid with 7.6 g.
  • the diazoniumsalt solution yields with a solution of cupric chloride in water and acetic acid which is saturated with sulfurdioxide the p-[2-(2-methoxy-5- chlorobenzamido)-ethyl]-benzenesulfonylchloride (crude product).
  • Example 10 According Example 1(a) one obtains from 17.8 g. 1-butyl-2-imino-imidazolidinc-hydrochloride in sodium hydroxide and 39.0 g. p-[2-(2-methoxy-5-chlorobenzamido)-ethyl]-benzene-sulfonylchloride the 1- ⁇ p-[2-(2- methoxy 5 chloro-benzamido)-ethyl]-phenylsulfonyl ⁇ - 2-imino-3-butyl-imidazolidine of M.P. 94-97 (from ethyl acetate).
  • Example 11 According Example 1(a) one obtains from 17.8 g. 1-tert.butyl-2-imino-imidazolidine-hydrochloride in so dium hydroxide and 39.0 g. p-[2-(2-methoxy-5-chlorobenzamido)-ethyl]-benzenesulfonylchloride the 1- ⁇ p[2- (2 methoxy 5 chlorobenzamido)-ethyl]-phenylsulfonyl ⁇ -2-imino-3-tert.butyl-imidazol1idine of M.P. -122.
  • the end product is purified by elution chromatography on silicagel with chloroform-ethanol (9:1) as elution solvent. From the first fractions one recovers unchanged starting material, from the last fractions the end product.
  • Example 12 According Example 1(a) one obtains from 20.4 g. 1-cyclohexyl-2-imino-imidazolidine-hydrochloride in sodium hydroxide and 39.0 g. p-[Z-(Z-methoxy-S-chlorobenzamido)-ethyl]-benzenesulfonylchloride the 1- ⁇ p-[2- (2 methoxy 5 chlorobenzamido) ethyl] phenylsulfonyl ⁇ -2-imino-3-cyclohexylimida.zolidine of M.P. 167- 170 (from methanol).
  • Example 1(a) one obtains from 17.8 g. 1-tert.butyl-2-imino-imidazolidine-hydrochloride in sodium hydroxide and 41.4 g. p-[2-(3,4,5-trimethoxy-benzamido) ethyl] benzenesulfonylchloride the 1- ⁇ p-[2-(3, 4,5 trimethoxy benzamido) ethyl]-phenylsulfonyl ⁇ -2- imino-3-tert.butyl-imidazolidine of M.P. -l32 (from ethyl acetate ether).
  • the sulfonylchloride which is used as starting material is prepared according to example 9(b).
  • Example 14 According Example 1(a) one obtains from 17.8 g. 1-tert.butyl-2-imino-imidazolidinehydrochloride in sodium hydroxide and 28.9 g. p-(2-butyrylamido-ethyl)- benzenesulfonylchloride the 1- [p- (2-butyrylamido-ethyl phenylsulfonyl] 2 -imino-3-tert.buty1- imidazolidine of M.P. 148149 (from ethyl acetate).
  • Example 15 (a) 38.1 g. 1 [p- (Z-amino-ethyl)-phenylsulfonyl]-2- imino-3-n-propyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. Thereafter to the reaction mixture is dropped at room temperature the solution of 9.3 g. propionic acid chloride in 100 ml. methylen chloride with in minutes.
  • n-butyrylchloride the 1-[p-(2-butyramido-ethyl)- phenyl sulfonyl] 2 imino 3 n propyl imidazolidine- H O, M.P. 114-116";
  • n-valeroylchloride the 1-[p-(2-valeramido-ethyl)- phenylsulfonyl]-Z-imino3-n-propyI-imidazolidine, M.P. 130-132;
  • Example 16 38.1 g. l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino- 3-isopr0pyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodiumsulfate are added 50.5 g. triethylamine. Thereafter one drops at room temperature a solution of 7.9 g. acetylchloride in 100 ml. methylenchloride within 20 minutes to the reaction solution.
  • Example 17 3 8.1 g. 1- [p-(Z-amino-ethyl) -pheny1sulfonyl]-2-imino- 3-isopropyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylen chloride solution which has been dried over sodiumsulfate are added 50.5 g. triethylamine. To this solution one drops at room temperature a solution of 9.3 g. propionic acid chloride in 100 ml. methylenchloride within 20 minutes. After stirring the solution for one hour at room temperature it is Washed with 100 ml.
  • Example 18 (a) 38.1 g. 1-[p-(2-amino-ethy1)-phenylsulfonyl]-2- imino-3-isopropyl-imidazolidine-dihydrochloride are dis solved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. Thereafter one drops to the solution at room temperature a solution of 10.7 g. butyric acid chloride in 100 ml. methylenchloride within 20 minutes.
  • n-valeric acid chloride the 1-[p-(2-valeramidoethyl)-phenylsulfonyl] 2 imino 3 isopropyl-imidazolidine, M.P. 123-124;
  • Example 19 (a) 39.7 g. 1 [P-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 butyl-imidazolidine-dihydrochloride are dis solved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution dried over sodium sulfate are added 50.5 g. triethylamine. Thereafter one drops to the solution at room temperature the solution of 7.9 g. acetyl chloride in 100 ml. methylene chloride within 20 minutes. After stirring the solution for 1 hour at room temperature it is washed with 100 ml.
  • valeric acid chloride the 1- [p-(2-valeramido-ethyl)- phenylsulfonyl] 2 imino 3 butyl-imidazolidine, M.P. 130;
  • caproyl chloride the 1-[p-(2-capronamido-ethyD- phenyl-sulfonyl] 2 imino 3 butyl-imidazolidine, M.P. 129-l30;
  • the obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtrated and evaporated.
  • the obtained oil (free base) is dissolved in ethanol and made acetic with saturated ethanolic hydrochloric acid.
  • the 1-[p-(2-amino-ethyl)-phenylsulfonyl] 2 imino-3-butyl-imidazolidine-dihydrochloride of M.P. 231-233 precipitates.
  • Example 20 41.5 g. 1-[(Z-amino-ethyl)-phenylsulfonyl]-2-irnino-3- isbutylimidazolidine dihydrochloride monohydrate are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution which has been dried over sodium sulfate are added 50.5 g. triethyl amine. Thereafter one drops at room temperature the solution of g. propionic acid chloride in 100 ml. methylene chloride within minutes to the solution. After stirring the solution for 1 hour at room temperature it is washed with 100 ml.
  • valeric acid chloride the 1-[p-(2-valeramido-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl imidazolidine, M.P. 137-140";
  • pivaloyl chloride the l-[p-(2-pivalamido-ethyl)- phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine, M.P. 165-167";
  • the obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtrated and evaporated.
  • the obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. On cooling and if desired diluting with ether the 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl imidazolidine-dihydrochloride-monohydrate precipitates, M.P. 151-152".
  • Example 21 39.7 g. l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino- 3-sec.-butyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution which has been dried over sodium sulfate are added 50.5 g. triethyl amine. Thereafter one drops to the solution at room temperature the solution of 12.9 g. valeric acid chloride in 100 ml. methylene chloride within 20 minutes.
  • propionyl chloride the 1-[p-(Z-propionamido-ethyl)-phenyl sulfonyl1-2-imino 3 sec.butyl-imidazolidine, M.P.
  • the obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtrated and evaporated.
  • the obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. On cooling and if desired diluting with ether the 1-[p-(2-amino-ethyl)- phenylsulfonyl]-2-imino 3 sec.butyl-imidazolidine-dihydrochloride precipitates, M.P. 250 (decomposition).
  • Example 22 41.5 g. 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino- 3-tert.butyl-imidazolidine-monohydrate are dissolved in 200 ml. water and the base liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution which has been dried over sodium sulfate are added 50.5 g. triethyl amine. Thereafter one drops at room temperature to the solution a solution of 7.9 g. acetyl chloride in 100 ml. methylene chloride within minutes. After stirring the solution for 1 hour at room temperature it is washed with 100 ml.
  • Example 23 (a) 41.5 g. 1 [p-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 tert.butyl-irnidazolidine-dihydrochloride-monohydrate are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution which has been dried over sodium sulfate are added 50.5 g. triethyl amine. Thereafter one drops to this solution at room temperature the solution of 13 g. isovaleric acid chloride in 100 ml. methylene chloride Within 20 minutes. After stirring the solution for 1 hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylene chloride. The
  • pivaloylchloride the 1-[p-(2-pivalamido-ethyl)- phenylsulfonyl] -2-imino-3 -tert.butyl-imidazolidine, M.P. 140-142;
  • the obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtratcd and evaporated.
  • the obtained oil (free base) is dissolved in ethanol and made acetic with ethanolic hydrochloric acid. On cooling and if desired diluting with ether the l-[p-amino-ethyl)-phenylsulfonyl]-2-imino- 3 tert.butyl imidazolidine dihydrochloride monohydrate precipitates, M.P. 232-234".
  • Example 24 40.9 g. 1- [p-(Z-amino-ethyl)-phenylsulfony1] -2-imino-3- cyclopentyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N
  • the obtained cloudy solution is made alkaline with concentrated sodium by droxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtrated and evaporated.
  • the obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. On cooling and if desired diluting with ether the 1-[p-(2- amino-ethyl)-phenyl-sulfonyl] 2 imino 3 cyclopentyl-imidazolidine-dihydrochloride, M.P. 270" (decomposition) precipitates.
  • Example 25 (a) 42.3 g. l [p-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 cyclohexyl imidazolidine dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried with sodium sulfate 50.5 g. triethylamine are added. To this solution are dropped at room temperature a solution of 9.3 g. propionic acid chloride in ml. methylenechloride within 20 minutes.
  • isovalerylchloride the l-[p-(2-isovaleramidoethyl)-phenylsulfonyl]-2-imino-3-cycl0heXy1- imidazolidine, M.P. 180-181 10.5 g. cyclopropane-carboxylic acid chloride the l-[p- (2-cyclopropane-carboxamidoethyl)-pheny1sulfonyl]- 2-imino-3-cyclohexyl-imidazolidine, M.P. 172-173;
  • the obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and three times extracted with methylenchloride; the organic phases are dried over sodium sulfate, filtrated and evaporated.
  • the obtained oil (free base) is dissolved in ethanol and made acidic with saturated hydrochloric acid in ethanol. On cooling and if desired diluting with ether the 1-[p-(2-amino-ethyl)- phenylsulfonyl] 2 imino 3 cyclohexyl-imidazolidinedihydrochloride, M.P. 247-250 precipitates.
  • Example 26 (a) According Example 25(a) one obtains from 43.7 g. 1 [p-amino-ethyl)-phenylsulfonyl]-2-imino-3-cycloheptyl-imidazolidine-dihydrochloride and 7.9 g. acetylchloride the 1 [p-(Z-acetamido-ethyl)-phenyl-sulfonyl]- 2-imino-3-cycloheptyl-imidazolidine, M.P. 166-167.
  • Example 27 (a) 41.1 g. 1-[p-(3-amino-propyl)-phenylsulfonyl]-2- imino-3-butyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. Thereafter one drops to this solution at room temperature the solution of 13 g. isovalerylchloride in ml. methylenchloride within 20 minutes.
  • the starting material 1- [p-(3-amino-propyl)-pheny1sulfonyl]-2-imino-3-butyl-imidazolidine-dihydrochloride can be obtained according two different methods:
  • Example 28 (a) 41.1 g. 1-[p-(3-amino-propyl)-phenylsu1fonyl]-2- imino 3-isobuty1-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. To this solution is dropped at room temperature a solution of 13 g. pivaloyl-chloride in 100 ml. methylenchloride within 20 minutes.
  • the obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. After evaporating one obtains the 1-[p-(3-aminopropyl)-phenylsulfonyl]-2-imino-3-isobuty1-imidazolidine dihydrochloride as an oil.
  • Example 29 41.1 g. 1-[p-(3-amino-propyl)-phenylsulfonyl]-2-imino- 3 tert.-butyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. To this solution is dropped at room temperature the solution of 18.2 g. 3,4-dimethyl-benzoylchloride in 100 ml. methylenchloride within 20 minutes.
  • the obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. After evaporating one obtains the l-[p-(3-amino-propyl)-phenylsulfonyl] 2 imino 3 tert.butyl imidazolidinedihydrochloride as an oil.
  • Example 30 (a) 41.1 g. 1-[p-(2 amino-ethyl)-phenylsulfonyl]-2 imino 3 butyl 4 methyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N-sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. To this solution is dropped at room temperature the solution of 12.7 g. valeryl chloride in 100 ml. methylenchloride within 20 minutes.
  • o-toluoylchloride the 1-[p-[2-(2-toluamido)-ethyl]- phenylsulfonyl] 2 imino 3 butyl 4 methyl-imidazolidine-hemihydrate, M.P. 103-105 23.7 g. o-bromobenzoylchloride the 1-[p-[2 (2 brombenzamido)-ethyl]-phenylsulfonyl] 2 imino-3-butyl- 4-methyl-imidazolidine, M.P. 100-102";
  • Example 31 (a) According Example 30 (a) one obtains from 41.1 g. 1-[p-(2 amino-ethyl)-phenylsulfonyl] 2 imino-3- butyl-S-methyl-imidazolidine and:
  • valerylchloride the 1-[p-(2 valeramido-ethyD- phenyl-sulfonyl] 2 imino 3 butyl-5-methylimidazolidine, M.P. 95-97;
  • Example 32 (a) According Example 30 (a) one obtains from 43.7 g. 1 [p (2 amino ethyl) phenylsulfonylJ-Z-imino- 3 cyclohexyl 5 methyl-imidazolidine-dihydrochloride and 10.7 g. butyrylchloride the l-[p-(2-butyramido-ethyl)- phenylsulfonyl] 2 imino 3 cyclohexyl 5 methylimidazolidine, M.P. 109-111".
  • Example 33 42.5 g. 1 [p (2 amino-ethyl)-phenylsulfonyl] 2- imino 3 butyl 4 ethyl-imidazolidine-dihydrochloride are dissolved in 300 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried with sodium sulfate are added 50.5 g. triethylamine. To this solution is dropped at room temperature the solution of 13 g. valeryl-chloride in 100 ml. methylenchloride within 20 minutes. After the solution has been stirred for one hour at room temperature it is washed with 100 ml.
  • pivaloylchloride the 1-[p-(2-pivalamido-ethyl)- phenyl-sulfonyl] -2-imino-3-butyl-4-ethylimidazolidine, M.P. 140-142;
  • Example 34 28 ml. 4 N sodium hydroxide and 4.3 g. ethylenimine are cooled to -10. To this solution is then added a suspension of 26.2 g. p-(Z-acetamidoethyl)-phenylsulfochloride in ml. acetone while stirring and cooling so that the temperature does not rise above 0. After adding is finished stirring is continued for 30 minutes at 0. Thereafter the cooling bath is removed and to the solution of the obtained 1-[p-(2-acetamido-ethyl)-phenylsulfonyl]-aziridine are added 100 ml. n-propylamine. The temperature rises to 40-50.
  • Example 35 reaction mixture is stirred for another hour and thereafter the excess of amine is distilled 01f on the rotary evaporator.
  • Example 36 28 ml. 4 N sodium hydroxide and 4.3 g. ethylenimine 5 are cooled to --10. Thereafter a suspension of 35.5 g. p- [2- 2-methoxybenzamido) -ethyl] -phenylsulfochloride in 100 ml. acetone while stirring and cooling is added so that the temperature does not rise above After dropping to is finished stirring is continued for '30 minutes at 0. Thereafter the cooling bath is removed and to the solution of the obtained [2-(2-methoxy-benzamido-ethyl)-phenylsulfonyll-aziridine are added 100 ml. n-propylamine. The temperature rises to 40-50.
  • Example 37 28 ml. 4 N sodium hydroxide and 4.3 g. ethylenimine are cooled to 10. Thereafter a suspension of 29.0 g. p-(2-butyryl-an1ido-ethyl)-phenylsulfochloride in 100 ml. acetone is added while stirring and cooling so that the temperature does not rise above 0". After dropping to is finished it is stirred for another 30 minutes at 0. Thereafter the cooling bath is removed and to the solution of the obtained 1-[p-(Z-butyramido-ethyl)-phenylsu1fonyl]-aziridine are added 100 m1. tert.butylamine. The temperature rises to 40-50.
  • the reaction mixture is stirred for another hour and thereafter the excess of amine is distilled off on the rotary evaporator.
  • the crystalline paste which contains besides sodium chloride the desired N -[p-(2-butyramido-ethyl)-phenylsulfonyl] N tert. butylethylendiamine is dissolved in 56 ml. 2 N sodium hydroxide and to this solution are added while stirring portionwise 10.6 g. bromocyan whereby the temperature is not allowed to rise above 40. After 1 hour the obtained compound is extracted with methylenchloride, washed with 20 ml. 2 N sodium hydroxide and twice with 100 ml. water.
  • Example 38 28 ml. 4 N sodium hydroxide and 5,7 g. propylenimine are cooled to Thereafter a suspension of 29.0 g. p- (2-butyramido-ethyl)-phenylsulfochloride in 100 ml. acetone is added while stirring and cooling so that the temperature does not rise above 0. After dropping to is finished the reaction mixture is stirred for 30 minutes at 0". Then the cooling bath is removed and to the solution of the obtained 1- [p-(butyramido-ethyl)-phenylsulfonyl]- Z-methyl-aziridine are added 100 ml. cyclohexylamine. The temperature rises to 40-50.
  • the reaction mixture is stirred for 1 hour and thereafter the excess of amine is distilled off on the rotary evaporator.
  • the crystalline paste which contains besides sodium chloride the desired 2-[p-(2 butyramido-ethyl)-phenylsulfonyl] 1 cyclohexylamino-propane is dissolved in 56 ml. 2 N sodiumhydroxide and to this solution is added while stirring portion wise 10.6 g. brom/cyan whereby the temperature is not allowed to rise above 40. After 1 hour the obtained compound is extracted with methylenchloride, washed with 20 ml. 2 N sodium hydroxide and twice with 100 ml. water.
  • Example 39 28 ml. 4 N sodium hydroxide and 5.7 g. propylenimine are, cooled to l0. Thereafter a suspension of 26.2 g. p-(2-acetamidoethyl)-phenylsulfochloride in 100 ml. acetone is added while stirring and cooling so that the temperature does not rise above 0. After dropping to is finished the reaction mixture is stirred for 30 minutes at 0". Then the cooling bath is removed and to the solution of the obtained l-[p (2 acetamido-ethyl)-phenylsulfonyl] 2 methyl aziridine are added ml. n-butylamine. The temperature rises to 40-50.
  • the reaction mixture is stirred for 1 hour and thereafter the excess of amine is distilled off on the rotary evaporator.
  • the crystalline paste which contains besides sodium chloride the desired 2 [p-( acetamido-ethyl)-phenylsulfonyl]-1-nbutylamino-propane is dissolved in 56 ml. 2 N sodium hydroxide and to this solution is added while stirring portion wise 10.6 g. bromocyan whereby the temperature is not allowed to rise above 40. After 1 hour the obtained compound is extracted with methylenchloride, washed with 20 ml. 2 N sodium hydroxide and twice with 100 ml. water.
  • Example 40 14.7 g. N-(Z-chlor-ethyl)-N-propyl-cyanamide and 27.0 g.
  • Example 43 (a) 38.8 g. N [p-(Z-propionamido-ethyl)-phenylsulfonyl] N 2 bromoethyl-cyanamide in 200 ml. ethanol and 19.8 g. cyclohexylamine are refluxed for 1 hour.
  • reaction mixture is evaporated on the rotary evaporator.
  • the residue is diluted with 50 ml. ethyl acetate and extracted two times with ml. 2 N hydrochloric acid.
  • the aqueous phase is made alkaline with 2 N sodium hydroxide and extracted twice with ml. methylenchloride.
  • the methylenchloride solution is washed with water, dried and evaporated.
  • the residue crystallizes from ethyl acetate and yields the pure l-[p-(Z-propionamido-etl1y1) phenylsulfonyl] 2 imino-3-cyclohexylimidazolidine-hemihydrate, M.P. -112".

Abstract

1-(P-AMINOALKYLSULFONYL) - 2 - IMINO - IMIDAZOLIDINES, SUBSTITUTED AT THE HETEROCYCLIC RING AND THE NITROGEN ATOM OF THE P-AMINOALKYL GROUP 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-(M-METHOXYBENZAMIDO) - ETHYL) - PHENYLSULPHONYL)-2-IMINO-3CYCLOHEXYL-IMIDAZOLIDINE.

Description

United States Patent 3,812,144 DERIVATIVES 0F p-AMINOALKYLBENZENE SULFONAMIDE Henri Dietrich, Arlesheim, and Claude Lehmann, Basel, Switzerland, assignors to Ciba-Geigy Corporation, Ardsley, N.Y. No Drawing. Filed Mar. 10, 1969, Ser. No. 805,843 Int. Cl. C07d 49/30 U.S. Cl. 260--309.7 10 Claims ABSTRACT OF THE DISCLOSURE 1-(paminoalkylphenylsulfonyl) 2 imino imidazolidines, substituted at the hcterocyclic ring and at the nitrogen atom of the p-aminoalkyl group 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 I-{p-[Z-(m-methoxy-benzamido) ethyl] phenylsulphonyl}-2-imino 3- cyclohexyl-imidazolidine.
DETAILED DISCLOSURE The present invention relates to new derivatives of paminoalkylbenzene sulfonamide, processes for their preparation, medicaments containing the new compounds and their use.
More particular, the present invention concerns compounds of the general formula I R is an alkyl group with not more than 12 carbon atoms, an alkenyl group with 3 to 5 carbon atoms, a cycloalkyl or cycloalkenyl group with not more than 7 carbon atoms or a phenylalkyl group with not more than 9 carbon atoms,
R; is hydrogen or an alkyl group with not more than 2 carbon atoms,
R is hydrogen, an alkyl group or chloroalkyl group with not more than 7 carbon atoms, an alkenyl group with not more than 5 carbon atoms, a cycloalkyl or cycloalkenyl group with not more than 8 carbon atoms, a phenyl group or a phenylalkyl or phenylalkenyl group with not more than 10 carbon atoms, wherein the phenyl group can be monoto tri-substituted by halogen of atomic number 35, trifluoromethyl groups, alkyl groups with not more than 4 carbon atoms, hydroxyl groups, alkoxy or alkylthio groups with not more than 12 carbon atoms, and
R is hydrogen or the methyl group, and their pharmaceutically acceptable acid addition salts.
The new compounds of the invention have been found to have hypoglycemic activities which are illustratively demonstrated in rats by orally administering the test compound to groups of 5 to 6 animals which have not been fed for 24 hours. Blood samples are taken from a vein of the animal and the blood sugar content is determined according to the method of Hagedorn-Jenson with an auto analyzer. Thus it is shown that 1-{p-[2-(m-methoxybenzamido)-ethyl]-phenylsulfonyl}-2-imino 3 cyclohexyl- Patented May 21, 1974 1- [P-( 2-butyramidoethy1) -phenylsulfonyl] -2-imino-3- propyl-imidazolidine, 1- [p- [2- (m-methoXy-b enzamido) -ethyl] -phenylsulfonyl] 2-imino-3 -propy1-imidazolidine, 1- p- (2-propionamido-ethy1) -phenylsulfonyl] -2-imino-3- isopropyl-imidazolidine, 1- [p-( Z-butyramidoethyl) -phenylsulfony1] -2-imino-3- isopropyl-imidazolidine, 1- [P- Z-acetamido-ethyl) -phenylsulfony1] -2-imino-3 butyl-imid azolidine, 1- [p- [2- Z-methyl-butyramido -ethy1] -phenylsulfonyl] -2- .imino-3 -n-b utyl-imidazolidine, 1- [p- 2-valeramido-ethyl -phenyl.sulfonyl] -2-imino-3- butyl-imidazolidine, 1- [p- 2 valeramido-ethyl) -phenylsulfonyl] -2-imino-3 'isobutyl-imidazoliline, 1- [p- [2- (2-methoxy-5-chloro-benzamido-ethy1] phenylsulfonyl] -2-imino-3 -isobntyl-imidazolidine, 1- [p- [2-cyclohexane-carboxamido -ethy1] phenylsulfonyl] -2-imino-3 -isobutyl-imidazolidine, 1- [p-( Z-acetamido-ethyl) -phenylsu1fonyl] -2-imino-3-sec.
butyl-imidazolidine, 1- [p- Z-propionamido-ethyl) -phenylsulfonyl] -2-imino-3- sec.butyl-imidazolidine, 1- [p-(2-butyramido-ethy1 -pheny1su1fonyl] -2-imino-3- sec. butyl-imid azolidine, 1- [p- (Z-butyramido-ethyl) -phenylsu1fonyl] -2-imino-3-tert.
butyl-imidazolidine, 1- [p- Z-isovaleramido-ethyl) -phenylsulfony1] -2-imino-3- tert. butyl-imidazolidine, 1- [p Z-butyramido-ethyl-phenylsulfonyl] -2-imino-3- cyclo-pentyl-imidazolidine, 1- [p- 2-valeramido-ethyl) -pheny1sulfonyl] -2-imino-3- cyclo-pentyl-imidazolidine, 1- [p- (2-cyclohexane-carboXamido-ethyl) -phenylsulfonyl]- 2-imino-3 -cyclopentyl-imidazolidine, 1- p- 2-formamido-ethyl) -phenylsulfonyl] -2-imino-3 cyclo-heXyl-imidazolidine, 1- [p- (2-acetamido-ethy1) -phenylsulfonyl] -2-imino-3- cyclo-hexylimidazolidine, 1- [p- [2- N-methyl-acetamido -propy1] -phenylsulfonyl] 2-imino-3-cyclohexyl-imid azolidine, 1- [p-(2-propionamido-ethy1) -phenylsulfonyl] -2-imino-3- cyclo-hexyl-imid azolidine, 1 [p- (Z-butyramido-ethyl) -phenylsulfony1]-2-imino-3- cyclo-hexyl-imid azolidine, 1- p-( 2-valeramido-ethy1) -phenylsulfonyl] -2-imino-3- cyclo-hexyl-imidazolidine, 1- [p- 2-isovaleramido-ethyl) -phenylsulfonyl] -2-imino-3- cyclo-hexyl-imidazo1idine, 1- [P- (2-benzamidoethyl -pheny1sulfonyl] -2-imino- 3-cycloheXyl-imidazolidine, 1 [p- [2- (m-methoxy-benzamido -ethyl] -phenylsulfonyl] 2-imino-3-cyclohexyl-imidazolidine, 1- [p- Z-cyclohexane-carboxamido-ethyl -phenylsulfonyl] -2-imino-3-cyclohexyl-imidazolidine, 1- [p-( Z-acetamido-ethyl) -phenylsulfonyl] -2-imino- 3-cyclohexyl-imidazolidine, 1- p-(Z-butyramido-ethyl) -phenylsulfonyl] -2-imino- 3 -cycloheptyl-imidazoli dine, 1- [p- (Z-butyramido-ethyl -phenyls ulfonyl] -2-imino- 3-cyclohexyl-imidazolidine, 1- [p- (Z-acetamido-ethyl) -phenylsulfonyl] -2-imino- 3-n-butyl-4-ethyl-imidazolidine, 1- [p- 2-acetamido-ethyl -phenylsu1fony1] -2-imino- 3 n-butyl-5 -methyl-imidazolidin-e,
1- [p- 2-valeramido-ethyl -phenylsulfonyl] -2-imino- 3-n-butyl-4-methyl-imidazolidine, and
1- [p- (2-valeramido-ethyl)-phenylsulfonyl] -2-imino- 3-n-butyl-4-ethyl-imidazolidine.
The toxicity of the compounds of the invention on oral administration as demonstrated in rats is of favorable low order. These properties render the compounds of the invention suitable for the treatment of diabetes.
In the compounds of general formula I, R can have the following meaning:
The substituent R as alkyl group can be the methyl or ethyl group and the substituent R as alkyl group can be the alkyl groups named under R with not more than 7 carbon atoms;
as chloroalkyl groups: the l-chloroethyl, l-chloropropyl,
l-chlorobutyl, l-chloropentyl, 1chlorohexyl, 2-chlorohexyl or the l-chloroheptyl group;
as cycloalkyl group: the cyclopropyl, cyclopropylmethyl,
cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, methylcyclohexyl, 4-methylcyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, cycloheptylmethyl, or the cyclooctyl group;
as cycoalkenyl groups: the 2-cyclopenten-l-yl, 2-cyclohexenl-yl, 3-cyclohexen-1-yl, 1-methyl-3-cyclohexen-lyl, 2-methyl-2-cyclohexen-1-yl, 3-methyl-2-cyclohexenl-yl, 2-cyclohepten-1-yl, 3-cyclohepten-1-yl, 2 cycloocten-l-yl or the 3-cycloocten-l-yl group;
as phenylalkyl or phenylalkenyl groups: the benzyl, phenethyl, phenylpropyl, phenylbutyl or the styryl group.
The phenyl group appearing in the definition of R may be monoto tri-substituted.
This substituent or these substituents can be the following groups:
as halogen: chlorine, fluorine or bromine;
as lower alkyl groups: the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl or the tertbutyl group; and,
as alkoxy or alkylthio groups: the methoxy, ethoxy, methylthio or the ethylthio group.
According to the inventive method for preparation, compounds of general formula I are prepared by reaction of a reactive functional derivative of a sulfonic acid of general formula II R4 (11) in which m, R and R have the meaning given under formula I with a compound of general formula III H-N N-Rl b t-H in which R and R have the meaning given under formula I and, if desired, the reaction product can be converted with an inorganic or organic acid into an addition salt.
As reactive functional derivative of a sulfonic acid of general formula II are suitable, e.g. a halogenide, particularly a chloride, or also an anhydride of general formula Ha in which m, R and R have the meaning given under formula I.
The reaction is preferably carried out in the presence of an inert organic solvent, which is miscible or inmiscible with water, in the presence or the absence of water. Suitable inert organic solvents are hydrocarbons, such as benzene, toluene or xylene, ether-like solvents such as ether, dioxane or tetrahydrofurane, chlorinated hydrocarbons such as rnethylenechloride and lower ketones such as acetone or rnethylethylketone. It is preferable to add an acid binding agent to the reaction solution. As such are suitable inorganic bases or salts, e.g. alkalimetal hydroxides, alkalimetal hydrogencarbonates, alkalimetal carbonates or alkalimetal phosphates, such as the corresponding sodium or potassium compounds. Additionally, there can also be used organic bases such as pyridine, trimethyl or triethylamine, N,N diisopropyl-ethylamine or collidine which are added in excess or which can also be used as solvent.
Starting materials of general formula II are compounds in which m, R and R are as defined under formula I. One group of sulfonylchlorides of the formula II, wherein R is a lower alkyl group, can be prepared by reaction of lower aliphatic carboxamides, which are substituted on the nitrogen atom by the phenylethyl or by the phenylpropyl group, with chlorosulfonic acid.
A second group of sulfonyl chlorides of general formula II, wherein R is an optionally substituted phenyl group may be prepared by reacting an optionally substituted benzoylchloride with p-nitro-phenethylamine or with p-nitrophenyl-propylamines to obtain the corresponding -N-(p nitro-phenethyl)- and N-(p-nitro-phenylpropyl)-benzam ides respectively. These nitro compounds are reduced with iron powder in hydrochloric acid tothe corresponding N- (p-amino-phenylethyl)- and N-(p-amino-phenylpropyl)- benzamides respectively. The reaction products are finally diazotised with sodium nitrite in hydrochloric acid and the diazonium salt solution is added to a solution of cupric chloride in water and glacial acetic acid which is saturated with sulfur dioxide.
According to a second inventive method for the preparation, compounds of general formula I are prepared by the reaction of an acid of general formula IV R, cooH V) in which R has the meaning given under formula I or a reactive functional derivative of such an acid with a compound of general formula V in which m, R R and 'R have the meaning given under formula I and, if desired, the compound obtained is converted with an inorganic or organic acid into an addition salt. The acylation and benzoylation respectively of compound V is carried out in a known manner, e.g. by reaction of the corresponding acid halogenides, -anhydrides or mixed-anhydrides, preferably in the presence of an acid binding or water binding agent or by treatment with reactive acid esters.
The reaction is preferably carried out in the presence of an inert organic solvent. Suitable inert organic solvents are hydrocarbons such as benzene, toluene or xylene, ether-like solvents such as ether, dioxane or tetrahvdrofurane, chlorinated hydrocarbons such as methylenechloride and lower ketones, such as acetone or methylethylketone. It is preferable to add to the reaction solution an acid binding agent, such as inorganic bases or salts, e.g. alkalimetal hydroxides, alkalimetal hydrogencarbonates, alkalimetal carbonates or alkalimetal phosphates, such as the corresponding sodium or potassium compounds. Additionally, there can be used organic bases such as pyridine, trimethylor triethylamine, N,N-diisopropylethylamine or collidine which can be used as solvent if added in excess.
To carry out these methods, an acid of general formula IV is reacted with a compound of general formula V in the presence of a carbodiimide such as dicyclohexylcarbodiimide in an inert solvent such as tetrahydrofuran. Lower alkyl esters, e.g. the methyl ester or the ethyl ester of the acids of general formula IV yield on heating with compounds of general formula V, the corresponding substituted amides of general formula I.
An alternative form of the method for the preparation of a halogenide or anhydride, in particular a mixed anhydride, is to react a carbonic acid half ester with a compound of general formula V, preferably in the presence of an acid binding agent, e.g. a strong tert. organic base like triethylamine, pyridine or s-collidine, which, if added in excess, can also serve as the reaction medium.
Reactive esters of acids of general .formula IV are the p-nitro-phenylester and the cyanomethylester.
The starting materials of general formula V mentioned above are obtained by hydrolysis of the compounds falling under the general formula Ia cm-oo l-cmHmQsorryL-Ri I H (Ia) in which m, R R and R have the meaning given under formula I.
According to another method for preparation, one obtains starting materials of general formula V by reaction of substituted p-(amino-alkyl)-benzenesulfonamides of general formula VI in which the symbols m and R have the meaning given under formula I with substituted N-2-bromoalkyl-cyanamides in alkaline medium [lit.: E. Miller et al., J. Am. Chem. Soc. 62, 2101 (1940)].
According to a third method for preparation, compounds of general formula I are prepared by condensation of compounds of general formula VII H,Rz H6:CH m-omwwnmQ-sm-h 1-12,
I'h III it. VII
in which m, R R R and K, have the meaning given under formula I, and
R is hydrogen, an arylmethyl, diarylmethyl or a triarylmethyl group, the methyl or the allyl group, with a reactive cyanic acid derivative under ring closure and optionally under cleavage of a R halogenide and, if desired, the compound obtained is converted with an inorganic or organic acid into an addition salt. R is preferably the benzyl, benzhydryl or the trityl group.
As reactive cyanic acid derivatives, there are most suitable cyanogenhalides, such as cyanogenchloride or cyanogenbromide or cyanic acid esters, particularly cyanic acid phenyl esters. The reaction is preferably carried out in the presence of an inert organic solvent which is miscible or immiscible with water, in the presence or absence of Water.
Suitable inert organic solvents are hydrocarbons such as benzene, toluene or xylene; lower alkanols, such as methanol or ethanol; ether-like solvents such as ether, dioxane or tetrahydrofuran; chlorinated hydrocarbons such as methylenechloride; lower ketones, such as acetone or methylethylketone; carbonic acid esters such as ethyl acetate; carbonic acid nitriles such as acetonitrile; or sulfones, such as tetrahydrothiophene-1,l-dioxide. The reaction can be carried out in the presence or absence of an acid binding agent. As acid binding agents there are suitable inorganic bases or salts such as alkalimetal hydroxides, alkalimetal hydrogen carbonates, alkalimetal carbonates or alkalimetal phosphates, e.g. the corresponding sodium or potassium compounds. Additionally, there can also be used calcium carbonate, calcium phosphate and magnesium carbonate.
As starting materials of general formula VIII, there are most suitable such compounds in which the symbols m, R R R or R -and R are in accordance with the symbols which are named after formula I to VIII. A group of such starting materials are N-(2-amino-ethyl) benzenesulfonamines, the benzene ring of which is substituted in para-positions by the alkylamido group According to a fourth inventive method for preparatron, compounds of general formula I are prepared by condensing a compound of general formula VIII 4 (VIII) in which m, R and K, have the same meaning as defined under formula I, with a reactive ester of a hydroxy compound of general formula IX in which R and R have the same meaning given under formula I under ring closure and, if desired, the compound obtained is converted with inorganic or organic acid into an addition salt.
Suitable reactive esters of hydroxy compounds of general formula IX are, e.g. halogenides, particularly chlorides or bromides, additional sulfonic acid esters, e.g. the 0- or p-toluene sulfonic acid ester or the methane sulfonic acid ester.
The condensation is preferably carried out in an solvent which is miscible or immiscible with water, in the presence or absence of water. As solvents, there can be used alkanols, e.g. butanol; ether-like solvents e.g. dioxane; diethyleneglycolmonomethyl ether, carbonic acid amides such as N,N-dimethylformamide' or sulfoxides, such as dimethylsulfoxide. It is preferable to carry out the condensation in the presence of an acid binding agent. As such can be used compounds which are named after the third method for preparation, also there can be used tert.organic bases such as, e.g. N,N-diisopropylethylamine.
As starting materials for the fourth method for preparation there can be used reactive esters which have been named before of a hydroxy compound of general formula IX which symbols R and R are in accordance with the symbols which are named after formula I. A group of bromides of general formula IX may be prepared if a l-alkyl-a ziridine [see A. Weissberger, Heterocyclic Compounds with Three and Four-Membered Rings, Part One, John Wiley Sons Inc., London (1964)] is reacted with cyanogen bromide in dioxane.
According to a fifth inventive method for preparation, compounds of general formula I are prepared by condensation and cyclization of a reactive ester of a compound of general formula X.
R4 EN in which m, R R and R have the meaning given under formula I with an amine of general formula XI R -NH in which R, has the same meaning given under formula I, if desired the compound obtained can be converted with inorganic or organic acids into an acid addition salt.
Suitable reactive esters of a hydroxy compound of general formula X are, e.g. halogenides, particularly chlorides or bromides, or sulfonic acid esters, particularly a benzene sulfonic acid ester which is substituted in paraposition by the amidoalkyl group The condensation is preferably done in a solvent. As such there are suitable the same solvents which are named in the fourth method for preparation.
The reaction is preferably carried out in the presence of an acid binding agent. As an acid binding agent there is most suitable an excess of bases of general formula XI.
As starting materials for this method for preparation, there are suitable reactive esters which have been named before of hydroxy compounds of general formula X, which symbols m, R R and R are in accordance with the symbols which are named after formula I.
A group of such compounds can be prepared in the following way.
One starts with aziridine and reacts this with cyanogen bromide in ether to obtain the N-(2-bromoethyl)-cyan amide; this cyanamide is condensed in acetone with a benzenesulfonylchloride which is substituted in paraposition by the group 123-0 Orr-mm...- it.
in the presence of diluted sodium hydroxide under separation of hydrogen chloride to yield the corresponding N- (Z-bromoethyl -N-cyanobenzenesulfonamide.
According to a sixth method, compounds of general formula I in which R is only hydrogen are prepared by formylation of compounds of general formula XII Ba ba H (XII) in which m, R R and "R have the same meaning given under formula I with chloral and, if desired, the compounds obtained can be converted with an inorganic or organic acid into an addition salt. The formylation is done according to Blicke, Am. Soc. 74, 3933 (1952) in an inert solvent, e.g. in dioxane, tetrahydrofuran, benzene, toluene or chlorinated hydrocarbons e.g. methylenechloride.
Starting materials of general formula XII are prepared according to the methods as they are described after the second method for preparation, preferably by hydrolysis of the corresponding substituted 1-[p-(2-acetamido-alkyl) -phenylsulfonyl]-2-imino-imidazolidines of general formula la.
The compounds of general formula I which are prepared according to the inventive method for preparation are converted if desired into the salts with inorganic or organic acids. The preparation of these salts can be done by reaction of compounds of general formula I with an equivalent amount of acid in a suitable aqueous-organic or inorganic solvent like methanol, ethanol, diethylether, chloroform or methylenechloride.
For use as medicaments instead of the free compounds of the general formula I, their pharmaceutically acceptable salts with acids may be used.
Suitable addition salts are salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethanesulfonic acid, p-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, hydroxysuccinic acid, tartaric acid, citric acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid, addition salts with blood sugar depressing sulfonyl ureas e.g. p-tolyl-sulfonyl-butylcarbamide, p chlorobenzenesulfonyl propyl-carbamide, and p- [2- (Z-methoxy-S-chlorobenzamido -ethyl] -phenylsulfonyl-cyclohexyl-carbamide.
The new compounds are preferably administered orally. The daily doses are between 30 and 300 mg. for adult patients with normal weight. Suitable dosage forms like drages and tablets, contain preferably 30 to 300 mg. of a compound of the invention, i.e. 20 to of a compound of general formula I, or a pharmaceutically acceptable acid addition salt thereof.
For their preparation, the active compound is combined, e.g. with a solid powdery carrier like lactose, saccharose, sorbitol, mannitol, starch, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, if desired under addition of sliding agents like magnesium or calcium stearate or polyethylene glycols to form tablets or drages cores.
The last-named are coated with concentrated solutions of sugar which may also contain some arabic gum, talc or titan dioxide or with a volatile organic solvent or mixtures of solvents which contain dissolved lacquer. It is possible to add to these coatings pigments to mark different doses of the active ingredients.
As other oral dosage forms there are suitable capsules of gelatine and a softening agent like glycerine. Plugged capsules contain the active ingredient preferably as granulate e.g. in mixture with fillers like corn starch and/or sliding agents like talc or magnesium stearate and, if desired, stabilizers like sodium meta-bisulphite (Na S O or ascorbic acid. In the soft capsules the active ingredient is preferably dissolved or suspended in suitable solvents like liquid polyethyleneglycols whereby if desired Stabilizers can be added.
The following methods for preparation describe the preparation of tablets and drages in more detail:
(a) 1000 g. of 1-[p-(Z-acetamido-ethyl)-phenylsulfonyl]-2-imino-3-butyl-imidazolidine are mixed together with 500 g. lactose and 270 g. of potato starch. The mixture is moistened with an aqueous solution of 8.0 g. gelatine and granulated through a filter. After drying, it is mixed together with 60.0 g. potato starch, 60.0 g. talc, 10.0 g. magnesium stearate and 20.0 g. colloidal silicon dioxide. After this, the mixture is pressed into 10,000 tablets, each of which has a weight of 200 mg. and contains mg. active ingredient, if desired, the tablets may be grooved for better adaptation to dosages.
'(b) From 1,000 g. l-p-[2-(3-methoxy-benzamido)- ethyl] phenyl sulfonyl-2-imino-3-cyclohexyl-imidazolidine, 345.0 g. lactose and the aqueous solution of 6.0 g. gelatine, a granulate is prepared which after drying is mixed together with 10.0 g. colloidal silicon dioxide, 40.0 g. talc, 40.0 g. potato starch and 5.0 g. magnesium stearate and pressed into 10,000 drage cores. These are coated afterwards with a concentrated syrup of 533.0 g. crystalline saccharose, 20.0 g. shellac, 75.0 g. gummi arabicum, 250 g. talc, 20 g. colloidal silicon dioxide and 20.5 g. 1-cyclohexyl-Z-imino-imidazolidine-hydrochloride and 30.4 g. p-(Z-valeramido-ethyl))-benzenesulfonylchloride the 1-[p-(2-valeramido-ethyl)-phenylsulfonyl] Z-imino-3-cyclohexyl-imidazolidine, H O, M.P. 154- 155;
20.5 g. 1-cyclohexyl-Z-imino-imidazolidine-hydrochloride and 30.4 g. p-(2-isovaleramido-ethyl)-benzenesulfonylchloride the 1[p-(2-isovaleramido-ethyl)-phenylsulfonyl]-2-imino 3 cyclohexyl-imidazolidine, M.P. 180- 181;
20.5 g. 1-cyclohexyl-2-imino-imidazolidine hydrochloride and 33.0 g. p-(2-cyclohexancarboxamido-ethyl)-benzenesulfonylchloride the 1 [p (2-cyclohexane-carboxamide-ethyl)-phenyl-sulfonyl] 2 imino-2-cyclohexylimidazolidine, M.P. 208-209;
20.37 g. 1-cyclohexyl-Z-imino-imidazolidine-hydrochloride and 35.4 g. p-[Z-(m-methoxy-benzamido)ethyl]- benzenesulfonylchloride the 1-[p-[2-m-methoxy-benz amide)-ethyl]-phenylsulfonyl] 2 imino-3-cyclohexylimidazolidine, M.P. 167-168;
18.1 g. 1-cycloheptyl-2-imino-imidazolidine and 24.8 g. p- (Z-formamido-ethyl)-benzenesulfonylchloride the 1- [p- (2-formamido-ethyl)-phenylsulfonyl] 2 imino 3- cycloheptylimidazolidiue, M.P. 130-133";
21.77 g. 1-cycloheptyl-Z-imino-imidazolidine-hydrochloride and 26.15 p-(2-acetamido-ethyl)-benzenesulfonylchloride the 1-[p-(2-acetamido-ethyl)-phenylsulfonyl] 2-imino-3-cycloheptylimidazolidine, M.P. 166-167";
21.8 g. 1-cycloheptyl-2-imino-imidazolidine-hydrochloride and 29.0 g. p-(Z-butyramido-ethyl)-benzenesulfonylchloride the 1-[p (2-butyramido-ethyl)-phenylsulfonyl] 2-imino-3-cycloheptyl-imidazolidine, M.P.
23.6 g. 1-butyl-5-methyl-2-imino-imidazolidine-hydrobromide and 26.15 g. p-(2-acetamido-ethyl)-benzenesulfonylchloride the l-[p-(2-acetamido-ethyl)-phenylsulfonyl]-2-imino-3-butyl-4-methyl-imidazolidine, M.P. 132-- 133";
25.0 g. l-butyl 5 ethyl-2-imino-imidazolidine-hydrobromide and 26.15 g. p-(2-acetamido-ethyl)-benzenesulfonylchloride the 1-[p-(Z-acetamido-ethyl)-phenylsulfonyl]-2-imino-3-butyl-4-ethyl imidazolidine, M.P. 111- 114;
19.2 g. 1-butyl-4-methyl-2-imino imidazolidine hydrochloride and 26.2 g. p-(2-acetamido-ethyl) -benzenesulfonylchloride the 1-[p-( 2 acetamidO-ethyD-phenylsulfonyl]-2-imino-3-butyl-5-methyl-imidazolidine, M.P. 98-99;
23.6 g. l-butyl-S-ethyl 2 imino-imidazolidine-hydrobromide and 30.4 g. p-(2-valeramido-ethyl)-benzenesulfonylchloride the 1-[P-(2 valeramido-ethyl)-phenylsulfonyl] 2-imino-3-butyl 4 ethyl-imidazolidine, M.P. 92-94;
18.3 g. 1-(2-methyl-cyclohexyl)-2-imino-imidazolidine and 24.8 g. p-(2formamido-ethyl)-benzenesulfonylchloride the l- [p- 2-formamido-ethyl -phenylsulfonyl] -2-imino- 3-(2-methyl-cyclohexyl)-imidazolidine, M.P. 127-129;
18.3 g. 1-(4-methylcyclohexyl)-2-imino-imidazolidine and 24.8 g. p-(2-formamido-ethyl)-benzenesulfonylchloride the 1- [p- 2-formamido-ethyl -phenylsulfonyl] -2-imino- 3-(4-methyl-cyclohexyl)-imidazolidine, M.P. 126-128";
26.4 g. 1-(4-methyl-cyclohexyl)-2-imino-imidazolidine-hydrochloride and 26.2 g. p-(Z-acetamido-ethyl)-benzenesulfouylchloride the 1-[p-(2 acetamido-ethyl)-phenylsulfonyl]-2-imino3-(4 methyl-cyclohexyl)-imidazolidine, MJP. 166167.
The p-(2 acetamido-ethyl) benzenesulfonylchloride which is used as starting material is obtained according to the following procedure:
(b) 16.3 g. N-phenethyl-acetamide are given portionwise while stirring to 35.0 g. chlorosulfonic acid. Thereafter the mixture is stirred for 2 hours at 60 and then poured on ice. The crystals are filtered off, washed with water and dried in vacuo. The p-(2-acetamido-ethyl)- 12 benzenesulfonylch'loride obtained is used as crude product. In analogous way one obtains the sulfonylchlorides used as starting material which are worked up as crude products:
from 14.9 g. N-phenylethyl-formamide and 35.0 g. chlorosulfonic acid the p-(2 formamido-ethyl) benzenesulfonylchloride;
from 17.7 g. 1-phenyl-2-acetamido-propane and 35.0 g.
chlorosulfonic acid the p-(2-acetamido-propyD-benzenesulfonylchloride;
from 18.7 g. N-(3-phenyl-propyl)-acetamide and 35.0 g.
chlorosulfonic acid the p-(3-acetamido-propyl)-benzenesulfonylchloride;
from 19.1 g. N-(3-phenyl-propyl)-N-methylacetamide and 35.0 g. chlorosulfonic acid the p-[2-(N-methylacetamidopropyl] -benzenesulfonylchloride;
from 17.7 g. N-phenethyl-propiouamide and 35.0 g. chlorosulfonic acid the p-(2-propionamido-ethyl)-benzenesulfonylchloride;
from 19.1 g. N-phenethyl-butyramide and 50.0 g. chlorosulfonic acid the p-(2-butyramido-ethyl)-benzenesulfonylchloride;
from 20.5 g. N-phenylethyl-valeramide and 35.0 g. chlorosulfonic acid the p-(2-valeramido-ethyl)-benzenesulfonylchloride;
from 20.5 g. N-phenylethyl-isovaleramide and 35.0 g.
chlorosulfonic acid the p-(2-isovaleramido-ethyl)-benzenesulfonylchloride;
from 23.1 g. N-phenylethyl-cyclohexane-carbamide and 35.0 g. chlorosulfonic acid the p-(Z-cyclohexane-carbamido-ethy1) -benzenesulfonyl-chloride;
Example 2 (a) According Example 1 (a J one obtains from 17.8 g. l-butyl-2-imino-imidazolidine-hydrochlorine in sodium hydroxide and 35.8 g. p-[2-(o-chlorobenzamido)-ethyl]- benzenesulfonylchloride the 1 {p [2 (o-chlorobenzamido) ethyl] phenylsulfonyl] 2 imino-3-butyl-- imidazolidine, M.P. 1551S7 (from isopropanol).
The sulfonyl chloride used as starting material is prepared according the following procedure:
(b) 17.6 g. o-chlorobenzoylchloride are added to 20.3
g g. p-nitro-phenethylamine-hydrochloride in ml. 5-n.-
sodium hydroxide and 50.0 g. ice. The N-(p-nitro-phenethyl)-o-chlorobenzamide crystallizes. It is suctioned off, washed with water, dried and used as crude product.
(c) To 30.5 g. of the obtained nitro compound according method (b) suspended in 85 ml. ethanol are added 1 ml. conc. hydrochloric acid with 16.0 g. iron powder it is refluxed for 12 hours. Then the reaction mixture is filtered and washed with ethanol. The filtrate is evaporated in vacuo and to the residue is added ethanolic hydrochloric acid. One obtains the N-(p-aminophenethyl)- o-chloro benzamidhydrochloride which is used as crude product.
(d) To 31.0 g. of the obtained hydrochloride according method (0) are added 100 ml. glacial acetic acid and 34 ml. concentrated hydrochloric acid. The solution is diazotized at 5 with 7.6 g. sodium nitrite which is dissolved in 30 ml. water. The obtained diazonium salt solution is given to a solution saturated with sulfodioxide of 4.0 g. cupric chloride, 7 ml. water and 80 ml. glacial acetic acid. A slight exothermic reaction at which at 35 nitrogen is split off starts. The reaction mixture is kept v for 2 hours. The p-[2-(o-chlorobenzamido)-ethyl]-benzenesulfonylchloride crystallizes. The crystals are suctioned OE and washed with water and used as crude product.
Example 3 13 phenylsulfonyl1-2-imino 3-tert.butyl-imidazolidine, M.P. 152-154 (from ethanol).
Example 4 (a) According Example 1 (a) one obtains from 17.8 g. 1-butyl-2-imino-imidazolidine-hydrochloride in sodium hydroxide and 35.4 g. p-[2-(o-methoxy-benzamido)- ethyl]-benzenesulfonylchloride the l-{-p-[2-o-methoxymethoxy-benzamido)-ethyl]-phenylsulfonyl}-2-imino 3- butyl-imidazolidine, M.P. 145-l46 (from methanol).
The sulfonylchloride used as starting material is prepared according to the following method:
(b) According Example 2 (b-d) one obtains starting with 17.1 g. o-methoxy-benzoylchloride with 20.3 g. pnitro phenethyl amine the N-(p-nitro-phenethyl))-omethoxy-benzamide of M.P. 149-150 (from acetic acid ethylester); 30.0 g. of this nitro compound are reduced with 16.0 g. iron powder to yield the N-(p-arninophenethyl)-o-methoxy-benzamide-hydrochloride of M.P. 211-214 (from methanol) of which are 30.5 g. diazotized in conc. hydrochloride acid with 7.6 g. sodium nitrite; the diazonium salt solution yields with a solution of cupric chloride in water and glacial acetic acid which is saturated with sulfodioxide the p-[2-(o-methoxybenzamido)-ethyl]-benzenesulfonylchloride which melts at 140-143 (crude products).
Example 5 (21) According Example 1 (a) one obtains from 16.4 g. 1 propyl 2 imino imidazolidine-hydrochloride in sodium hydroxide and 35.4 g. p-[Z-(m-methoxy-benzamido)-ethyl]-benzenesulfonylchloride the 1-{p-[2-(mmethoxy-benzamido)-ethyl]-phenylsulfonyl} 2 imino-3- propyl imidazolidine, M.P. 144-147 (from ethyl acetate).
The sulfonylchloride used as starting material is prepared according the following procedure:
(b) According Example 2 (b-d) one obtains starting with 17.1 g. m-methoxy-benzoylchloride with 20.3 g. pnitro-phenethylamine the N-(p-nitro-phenethyD-m-methoxy-benzamide M.P. 151-152 (from ethyl acetate); 30.0 g. of this nitro compound are reduced with 16.0 g. iron powder to yield the N-(p-amino-phenethyl)-n-methoxybenzamide-hydrochloride, M.P. 205-209 of which 30.5 g. are diazotized in concentrated hydrochloric acid with 7.6 g. sodium nitrite; the diazonium salt solution yields with a solution of cupric chloride in water and glacial acetic acid which is saturated with sulfurdioxide the p-[Z- (m methoxy-benzamido)-ethyl]-benzenesulfonylchloride (crude product).
Example 6 According Example 1 (a) one obtains from 17.8 g. 1- butyl 2 imine-imidazolidine-hydrochloride in sodium hydroxide and 35.4 g. p-[2-(m-methoxy-benzamido)- ethyl] benzenesulfonylchloride the l-{p-[2-'(m-methoxybenzamido) ethyl] phenylsulfonyl} 2 imino-3-butylimidazolidine, M.P. 137-141 (from methanol).
Example 7 According Example 1 (a) one obtains from 17.8 g. 1- tert.butyl 2 imino imidazolidine-hydrochloride in sodium hydroxide and 35.4 g. p-[Z-(m-methoxy-benzamido) ethyl]-benzenesulfonylchloride the l-{p-[2-(mmethoxy benzamido) ethyl]-phenylsulfonyl}-2-imino 3-tert.-butyl-imidazolidine of M.P. 134-136 (from ethyl acetate).
Example 8 (a) According Example 1 (a) one obtains from 17.8 g. 1tert.butyl-2-imino imidazolidine hydrochloride in sodium hydroxide and 33. 8 g. p-[2-(o-toluamido)-ethyl]- benzenesulfonylchloride the l-{p[2-(o-toluamido)-ethyl]- phenylsulfonyl} 2 imino 3 tert.butyl-imidazolidine of M.P. 160-161.
The sulfonylchloride used as starting material is prepared according to the following procedure:
(b) According Example 2 (b-d) one obtains starting with 15.5 g. o-toluoylchloride with 20.3 g. p-nitro-phenethylamine the N-(p-nitro phenethyl) p toluamide (crude products); 28.4 g. of this nitro compound are reduced with 16.0 g. iron powder to yield the N-(p-aminophenethyl) o-toluamide-hydrochloride (crude product) of which 28.4 g. are diazotized in conc. hydrochloride acid with 7.6 g. sodium nitrite; the diazonium salt solution yields with a solution of cupric chloride in water and glacial acetic acid which is saturated with sulfurdioxide the p [2-(o-toluamido)-ethyl]-benbenesulfonylchloride (crude product).
Example 9 (a) According Example 1(a) one obtains from 13.6 g. l-methyl-2-imino-imidazolidinerhydrochloride in sodium hydroxide and 39.0 g. p-EZ-(Z-methoxy-S-chlorobenzamido)-ethyl]-benzenesulfonylchloride the 1-{p-[2- (Z-methoxy 5 chloro-benzamido)-ethyl]-phenylsu]fonyl}-2-irnino-3-methyl-imidazolidine of M.P. 140-14l (from ethyl acetate).
The sulfonylchloride used as starting material is prepared according to the following procedure:
(b) According Example 2(b-d) one obtains starting with 20.6 g. 2-m'ethoxy-S-chlorobenzoylchloride with 20.3 g. p-nitro-phenethylamine the N-(p-nitrdphenethyD-Z- methoxy-S-chloro-benzamide, M.P. 158-160"; 30.0 g. of this nitro compound are reduced with 16.0 g. iron powder to yield the N-(p-amino-phenethyl)-2-methoxy-5-chlorobenzamide-hydrochloride (crude product) of which 34.0 g. are diazotized in conc. hydrochloride acid with 7.6 g. sodium nitrite; the diazoniumsalt solution yields with a solution of cupric chloride in water and acetic acid which is saturated with sulfurdioxide the p-[2-(2-methoxy-5- chlorobenzamido)-ethyl]-benzenesulfonylchloride (crude product).
Example 10 According Example 1(a) one obtains from 17.8 g. 1-butyl-2-imino-imidazolidinc-hydrochloride in sodium hydroxide and 39.0 g. p-[2-(2-methoxy-5-chlorobenzamido)-ethyl]-benzene-sulfonylchloride the 1-{p-[2-(2- methoxy 5 chloro-benzamido)-ethyl]-phenylsulfonyl}- 2-imino-3-butyl-imidazolidine of M.P. 94-97 (from ethyl acetate).
Example 11 According Example 1(a) one obtains from 17.8 g. 1-tert.butyl-2-imino-imidazolidine-hydrochloride in so dium hydroxide and 39.0 g. p-[2-(2-methoxy-5-chlorobenzamido)-ethyl]-benzenesulfonylchloride the 1-{p[2- (2 methoxy 5 chlorobenzamido)-ethyl]-phenylsulfonyl}-2-imino-3-tert.butyl-imidazol1idine of M.P. -122.
The end product is purified by elution chromatography on silicagel with chloroform-ethanol (9:1) as elution solvent. From the first fractions one recovers unchanged starting material, from the last fractions the end product.
Example 12 According Example 1(a) one obtains from 20.4 g. 1-cyclohexyl-2-imino-imidazolidine-hydrochloride in sodium hydroxide and 39.0 g. p-[Z-(Z-methoxy-S-chlorobenzamido)-ethyl]-benzenesulfonylchloride the 1-{p-[2- (2 methoxy 5 chlorobenzamido) ethyl] phenylsulfonyl}-2-imino-3-cyclohexylimida.zolidine of M.P. 167- 170 (from methanol).
Example 1.3
According Example 1(a) one obtains from 17.8 g. 1-tert.butyl-2-imino-imidazolidine-hydrochloride in sodium hydroxide and 41.4 g. p-[2-(3,4,5-trimethoxy-benzamido) ethyl] benzenesulfonylchloride the 1-{p-[2-(3, 4,5 trimethoxy benzamido) ethyl]-phenylsulfonyl}-2- imino-3-tert.butyl-imidazolidine of M.P. -l32 (from ethyl acetate ether).
The sulfonylchloride which is used as starting material is prepared according to example 9(b).
Example 14 According Example 1(a) one obtains from 17.8 g. 1-tert.butyl-2-imino-imidazolidinehydrochloride in sodium hydroxide and 28.9 g. p-(2-butyrylamido-ethyl)- benzenesulfonylchloride the 1- [p- (2-butyrylamido-ethyl phenylsulfonyl] 2 -imino-3-tert.buty1- imidazolidine of M.P. 148149 (from ethyl acetate).
Example 15 (a) 38.1 g. 1 [p- (Z-amino-ethyl)-phenylsulfonyl]-2- imino-3-n-propyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. Thereafter to the reaction mixture is dropped at room temperature the solution of 9.3 g. propionic acid chloride in 100 ml. methylen chloride with in minutes. After stirring the solution for one hour at room temperature it is washed with 100 m1. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylen chloride. The combined methylenchloride phases yield after drying with sodium sulfate, filtrating and evaporating l-[p-(2-propionamido-ethyl)- phenylsulfonyl]-2-imin0-3-n-propyl-imidazolidine which melts at 127-129" after recrystallization from ethyl acetate.
In analogus way one obtains from 38.1 g. 1-[p-(2- amino ethyl) phenylsulfonyl] 2 imino-3-n-propylimidazolidine-dihydrochloride and:
9.3 g. propionyl-chloride the 1-[p-(2-propionamido-ethyl) phenylsulfonyl] 2 imino-3-n-propyl-imidazolidine H O=130-134;
10.7 g. n-butyrylchloride the 1-[p-(2-butyramido-ethyl)- phenyl sulfonyl] 2 imino 3 n propyl imidazolidine- H O, M.P. 114-116";
12.1 g. n-valeroylchloride the 1-[p-(2-valeramido-ethyl)- phenylsulfonyl]-Z-imino3-n-propyI-imidazolidine, M.P. 130-132;
12.1 g. isovaleric acid chloride the 1-[p-(2-isovaleramidoethyl)-phenylsulfonyl] 2 imino-3-n-propyl-imidazolidine, M.P. 135-136;
10.5 g. cyelopropancarbonic acid chloride the 1-[p-(2- cyclopropancarboxamido ethyl) phenylsulfonyl] 2- imino-3-n-propyl-imidazolidine, M.P. 142143;
14.7 g. cyclohexylcarbonic acid chloride the 1-[p-(2-cyclohexylcarboxamido-ethyl)-phenylsulfonyl] 2 imino-3- n-propyl-imidazolidine, M.P. 144146;
15.5 g. o-toluoylchloride the 1-[p-[2-(2-toluamido)-ethyl] phenylsulfonyl]-2-imino-3-n-propyl-imidazolidine, M.P. 114-116;
17.5 g. o-chlorbenzoylchloride the 1-[p-[2-(2-chlorbenzamido) ethyl] phenylsulfonyl] 2 imino 3 n propyl-imidazolidine, M.P. 145-146;
21.9 g. o-brombenzoylchloride the 1-[p-[2-(2-br0mbenzamido)-ethyl]-phenylsulfonyl] 2 imino-3-n-propylimidazolidine, M.P. 137-438;
16.9 g. 2,5-dimethylbenzoylchloride the 1-[p-[2-(2,5-dimethylbenzamido)-ethy1]-phenylsulfonyl] 2 imino- 3-n-propyl-imidazolidine, M.P. 1 17-1 18 14.1 g. m-chlorobutyric acid chloride the 1-[p-(2-a-ch1orobutylamido-ethyl)-phenylsulfonyl] 2 imino-3-n-propyl-imidazolidine, M.P. 123-124;
17.0 g. m-methoxy-benzoylchloride the 1 [p-[2-(3-methoxybenzamido)-ethyl]-phenylsu1fonyl] 2 imino-3- propyl-imidazolidine, M.P. 144-147";
10.5 g. l-meth-acryloylchloride the 1 [p-[2 (l-methacryrylamido)-ethyl]-phenylsulfonyl] 2 imino-3-propyl-imidazolidine, M.P. 139140;
16 21.0 g. 2,4-dichlorobenzoylchloride the 1-[p-[2-(2,4-dichlorobenzamido)-ethyl]-phenylsulfonyl] 2 imino-3- propyl-imidazolidine, M.P. 122-124";
(b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl] 2 imino-3-pr0pyl-imidazolidine-dihydrochloride is obtained according to two methods:
(1) 35.2 g. l-[p-(Z-acetamino-ethyl)-phenyl-sulfonyl]- 2-imino-3-propyl-imidazolidine are dissolved in 370 ml. 2 N hydrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuo to dryness and the obtained oil dissolved in ethanol. On cooling the 1-[p-(2-amino-ethyl-benzenesulfonyl]-2-imino-3- propyl)-imidazolidine-dihydrochloride crystallizes, M.P. 255256.
(2) A mixture of ml. dimethylsulfoxide, 11.2 g. pulverized potassium hydroxide, 23.65 g. p-(Z-aminoethyl)-phenyl-sulfonamide-hydrochloride [1it.: E. Miller et al., J. Am. Chem. Soc. 62, 2101 (1940)] and 16 g. N- (2-chlor-ethyl)-N-propyl-cyanamide is heated while stirring for one hour in an oil bath of After cooling one pours on water. The obtained cloudy solution is made alkaline with cone. sodium hydroxide, saturated with sodium chloride and extracted three times with methylenchloride; the organic phases are dried over s0- diumsulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. On cooling and if desired diluting With ether the 1-[-(2-amino-ethyl)- phenylsulfonyl] 2 imino-3-propyl-imidazolidinedihydrochloride of M.P. 255256" precipitates.
Example 16 38.1 g. l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino- 3-isopr0pyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodiumsulfate are added 50.5 g. triethylamine. Thereafter one drops at room temperature a solution of 7.9 g. acetylchloride in 100 ml. methylenchloride within 20 minutes to the reaction solution. After stirring for one hour at room temperature, it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylenchloride. The combined methylenchloride phases yield after drying with sodiumsulfate, filtrating and evaporating the 1- [p-(Z-acetamido-ethyl)-phenylsulfonyl]-2-imino 3 isopropyl-imidazolidine which melts after recrystallization from ethyl acetate at 133-135.
Example 17 3 8.1 g. 1- [p-(Z-amino-ethyl) -pheny1sulfonyl]-2-imino- 3-isopropyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylen chloride solution which has been dried over sodiumsulfate are added 50.5 g. triethylamine. To this solution one drops at room temperature a solution of 9.3 g. propionic acid chloride in 100 ml. methylenchloride within 20 minutes. After stirring the solution for one hour at room temperature it is Washed with 100 ml. 2 N sodiumhydroxide and twice with 100 ml. Water. The aqueous phases are extracted twice with methylenchloride. The combined methylenchloride phases yield after drying with sodiumsulfate, filtrating and evaporating the 1 [p-(2-propionamido-ethyl)-phenylsulfonyl]-2- imino-3-isopropyl-imidazolidine which after recrystallizazation melts at 111-112".
Example 18 (a) 38.1 g. 1-[p-(2-amino-ethy1)-phenylsulfonyl]-2- imino-3-isopropyl-imidazolidine-dihydrochloride are dis solved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. Thereafter one drops to the solution at room temperature a solution of 10.7 g. butyric acid chloride in 100 ml. methylenchloride within 20 minutes. After stirring the solution for one hour at room temperature it is washed with 100 ml. 2 N sodium hydroxideand twice with 100 ml. water. The aqueous phases are extracted twice with methylenchloride. The combined methylen chloride phases yield after drying with sodium sulfate, filtrating and evaporating the 1-[p-(2-butyramido-ethyl)- phenylsulfonyl-Z-imino 3 isopropyl-imidazolidine which after recrystallization from ethyl acetate melts at 139- 140".
In analogous way one obtains from 38.1 g. 1-[p-(2- amino-ethyl)-phenylsulfonyl] 2 imino 3 isopropylimidazolidine-dihydrochloride and:
10.7 g. butyrylchloride the 1 [P-(2-butyramido-ethyl)- phenylsulfonyl] 2 imino 3 isopropyl-imidazolidine, M.P. 139-140;
12.1 g. n-valeric acid chloride the 1-[p-(2-valeramidoethyl)-phenylsulfonyl] 2 imino 3 isopropyl-imidazolidine, M.P. 123-124;
10.5 g. cyclopropancarbonic acid chloride the 1-[p-(2- cyclopropancarboxamido ethyl) phenylsulfonyll-Z- imino-3-isopropyl-imidazolidine, M.P. 114-1 16 15.5 g. o-toluachloride the 1-[p-[2-(2-toluamido-ethyl1- phenyl-sulfonyl] 2 imino 3 isopropyl-imidazolidine, M.P. 132-134:
17.5 g. o-chlorbenzoylchloride the 1-[p-[2-(2-chlorbenzamido)-ethyl]-phenylsulfonyl] 2 imino 3 isopropyl-imidazolidine, M.P. 132-134";
10.5 g. l-methacryloylchloride the 1-[p-[2-(1-methacrylamido)-ethyl]-phenylsulfonyl] 2 imino 3 isopropyl-imidazolidine-lH O, M.P. 106-107";
(b) The starting material l-[p-(2-amino-ethyl)-phenylsulfonyl[2-amino 3 isoproyyl-imidazolidine-d'ihydrochloride is obtained according to two methods for preparation:
1) 35.2 g. 1-[p-(2-acetamino-ethyl)-phenylsulfonyl[- Z-amino 3 isopropyldmidazolidine are dissolved in 370 ml. 2 N. hydrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuo to dryness, and the oil obtained dissolved in ethanol. On cooling the 1[p (2 amino-ethyl)-phenylsulfonyl]-2-imino- 3 isopropyl imidazolidine-dihydrochloride crystallizes, M.P. 249-250.
(2) A mixture of 100 ml. dimethylsulfoxide, 11.2 g. pulverized potassium hydroxide, 23.65 g. p-(Z-aminoethyl)-phenylsulfonamide-hydrochloride [lit.: E. Miller et al., J. Am. Chem. Soc. 62, 2101 (1940)] and 16 g. N- (2-chloro-ethyl)-N-isopropyl-cyanamide are refluxed for one hour in oil bath of 110. After cooling one pours on water. The obtained cloudy solution is made alkaline with cone. sodium hydroxide, saturated with sodium chloride and extracted three times with methylen chloride; the organic phases are dried over sodium sulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloride acid. n cooling and if desired diluting with ether the 1-[p-(Z-amino-ethyl)-phenyl-sulfonyl] 2 imino- 3-isopropyl-imidazolidine-dihydrochloride of M.P. 249- 250 precipitates.
Example 19 (a) 39.7 g. 1 [P-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 butyl-imidazolidine-dihydrochloride are dis solved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution dried over sodium sulfate are added 50.5 g. triethylamine. Thereafter one drops to the solution at room temperature the solution of 7.9 g. acetyl chloride in 100 ml. methylene chloride within 20 minutes. After stirring the solution for 1 hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide and twice with ml. water. The aqueous phases are extracted twice with methylene chloride. The combined methylene chloride phases yield after drying with sodium sulfate, filtrating and evaporating 1-[p-(2- acetamido ethyl) phenylsulfonyl] 2 imino-3-butylimidazolidine which after recrystalisation from ethyl acetate melts at -131.
In analogous way one obtains from 39.7 g. 1-p-(2- amino-ethyl) phenylsulfonyl] 2 imino 3 butylimidazolidine-hydrochloride and 10.7 g. butyrylchloride the 1 [-(2-butyramido-ethyl)- phenylsulfonyl] 2 imino 3 butyl-imidazolidine, M.P. 123-124;
13.0 g. 2 methyl butyrylchloride the l-[p-(a-methylbutyr-amido-ethyl)-pheny1sulfonyl] 2 imino-S-butylimidazolidine, M.P. 114-116";
13.0 g. valeric acid chloride the 1- [p-(2-valeramido-ethyl)- phenylsulfonyl] 2 imino 3 butyl-imidazolidine, M.P. 130;
13.0 g. isovaleric acid chloride the 1-[p-(2-isovaleramidoethyl)-phenylsu1fonyl] 2 imino 3 butyl-imidazolidine, M.P. 130-1305";
14.5 g. caproyl chloride the 1-[p-(2-capronamido-ethyD- phenyl-sulfonyl] 2 imino 3 butyl-imidazolidine, M.P. 129-l30;
17.5 g. caprylic acid chloride the 1 [p-(2-octanamidoethyl)-phenyl-sulfonyl] 2 imino 3 butyl-imidazolidine, M.P. 130-131";
18.9 g. o-chloro-benzoyl chloride the 1 [p [2-(2-chlorobenzamido)-ethyl]-phenylsulfonyl] 2 imino 3 -nbutyl-imidazolidine, M.P. 155-157;
17.1 g. o-methoxybenzoyl chloride the 1 [p-[2-(2-methoxybenzamido)-ethyl]-phenylsulfonyl] 2 imino 3- butyl-imidazolidine, M.P. -146;
18.8 g. p chlorphenyl acetyl chloride the 1-[p('2-[2- (4-chlorphenyl) acetamido) ethyl]-phenylsulfonyl]- 2-imino-3-butyl-imidazolidine, M.P. 1 63-1642 19.7 g. 2 phenyl butyryl chloride the 1- [p-[2-(2-phenylbutyramido) ethyl] phenylsulfonyl] 2 imino-3- butyl-imidazolidine, M.P. 127-128;
12.5 g. 1 ethyl propionyl chloride the 1-[p-[2(1-ethylpropionamido) ethyl] phenylsulfonyl] 2 imino-3- butyl-imidazolidine, M.P. 125-126";
9.2 g. acrylolyl chloride the 1 [p (2-acrylamido-ethyl)- phenyl-sulfonyl] 2 imino 3 butyl-imidazolidine, M.P. .153-154;
22.1 g. 2 methoxy 5 chloro-benzoyl chloride the 1- [p-[2-(2 methoxy 5 chloro-benzamido) ethyl]- phenylsulfonyl1-2-imino-3 butyl-imidazolidine, M.P. 94-97;
18.0 g. B-methoxy benzoyl chloride the 1 [P-[2-(3- methoxy-benzamido) ethyl] phenylsulfonyl] 2 imino-3-butyl-imidazolidine, M.P. 139-141;
16.5 g. 1 methyl 3 cyclohexene carbonic acid chloride the l- [p-[2-(1 methyl 3 cyclohexene carboxamido) ethyl] phenyl sulfonyl] 2 imino-3-butylimidazolidine, M.P. 149-l50;
the 1-[p-[2 (3,4 dimethoxy benzamido) ethyl]- phenylsulfonyl] 2 imino 3 butyl imidazolidine, M.P. 169-170;
imino 3-buty1-imidazolidine-dihydrochloride crystallizes,
(2) A mixture of 100 ml. dimethylsulfoxide, 11.2 g. pulverized potassium hydroxide, 23.65 g. p-(2-amino- 19 ethyl)-benzene-sulfonamide hydrochloride [lit.: E. Miller et al., J. Am. Chem. Soc. 62, 2101 (1940)] and 16 g. N-+(2-chlor-ethyl)-N-butyl-cyanamide are heated in an oil bath of 110 while stirring for 1 hour. After cooling one pours on water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acetic with saturated ethanolic hydrochloric acid. On COOling and if desired diluting with ether the 1-[p-(2-amino-ethyl)-phenylsulfonyl] 2 imino-3-butyl-imidazolidine-dihydrochloride of M.P. 231-233 precipitates.
Example 20 41.5 g. 1-[(Z-amino-ethyl)-phenylsulfonyl]-2-irnino-3- isbutylimidazolidine dihydrochloride monohydrate are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution which has been dried over sodium sulfate are added 50.5 g. triethyl amine. Thereafter one drops at room temperature the solution of g. propionic acid chloride in 100 ml. methylene chloride within minutes to the solution. After stirring the solution for 1 hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide, and twice with 100 ml. water. The aqueous phases are extracted twice with methylene chloride. The combined methylene chloride phases yield after drying with sodium sulfate, filtrating and evaporating the 1-[p-(2-propionamidoethyl) phenylsulfonyl]-2-amino-3-isobutyl-imidazolidine, which melts at 140-142 after recrystallization from ethyl acetate.
In analogous way one obtains from 41.5 g. 1-[p-(2- amino ethyl)-phenylsulfonyl] 2 amino 3-isobutylimidazolidine-dihydrochloride-monohydrate and:
11.7 g. butyric acid chloride the I-[p-(Z-butyramido-ethyl)-phenyl sulfonyl]-2-imino-3-isobutyl-imidazolidine, M.P. 138-139";
13.0 g. valeric acid chloride the 1-[p-(2-valeramido-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl imidazolidine, M.P. 137-140";
13.0 g. isovaleric acid chloride the 1-[p-(2-isovaleramidoethyl)-phenylsulfonyl]-2-imino 3 isobutyl-imidazolidine, M.P. ISO-152;
13.0 g. pivaloyl chloride the l-[p-(2-pivalamido-ethyl)- phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine, M.P. 165-167";
14.4 g. hexanoyl chloride the 1-[p-(2-hexanamido-ethyl)- phenylsulfonyl] -2-imino-3-isobuty1-imidazolidine, M.P. 139-140;
10.5 g. cyclopropan-carbonic acid chloride the 1-[p-(2- cyclopropan carboxamido ethyl)-phenylsulfonyl]-2- imino-3-isobutylimidazolidine, M.P. 163-164 15.6 g. cyclohexan-carbonic acid chloride the 1-[p-(2-cyclohexan-carboxamido-ethyl -phenyl-sulfonyl] -2-imino- 3-isobutylimidazolidine, M.P. 175-177;
16.7 g. o-toluoyl chloride the 1-[p-(2-toluamido-ethyl)- phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine, M.P. 138-140;
18.4 g. o-methoxy-benzoyl chloride the 1-[p[2-(2-methoxy-benzamido) -ethyl]-phenylsulfonyl] 2 imino-3- isobutyl-imidazolidine, M.P. 110-11 1;
22.3 g. 2-methoxy-5-chloro-benzoyl chloride the 1-[p-[2- (methoxy-5-chloro-benzamido -ethyl] -phenylsulfonyl] 2-imino-3-isobutyl-imidazolidine, M.P. 117-1 19 18.3 g. 3,4-dimethyl-benzoyl chloride the 1-[p-[2-(3,4- dimethyl benzamido)-ethyl]-pheny1sulfonyl]-2-imino- 3-isobutyl-imidazolidine, M.P. 1585-160;
23.7 g. o-bromine-benzoyl chloride the 1- [p-[2-(2-bromobenzamido)-ethyl]-phenylsulfonyl] 2 imino-3-isobutyl-imidazolidine, M.P. 158-160;
20.4 g. p-chlorine-phenyl-acetyl chloride the 1-[p-[2-(4- chloro phenyl acetamido)-ethyl]-phenylsulfonyl]-2- imino-3-isobutyl-imidazolidine, M.P. 175-176";
22.4 g. 2,4-dichlorine-benzoyl chloride the 1[p-[2-(2,4- dichloro benzamido)-ethyl]-phenylsulfonyl]-2-amino- 3-isobutyl-imidazolidine, M.P. 102.5-104";
10.2 g. acetanhydride the l-[p-(2-acetamido-ethyl)-phenylsulfonyl]-2-imino 3 isobutyl-imidazolidine, M.P. 149-151;
(a) The starting material 1-[p-(2-amino-ethyl)pheny1- sulfonyl]-2-imino 3-isobutyl imidazolidine dihydrochloride-monohydrate is obtained after two methods:
(1) 36.65 g. 1-[p-(2-acetamino-ethyl)-phenylsulfony1]- 2-imino-3-isobutyl-imidazolidine are dissolved in 370 ml. 2 N hydrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuum to dryness and the obtained oil dissolved in ethanol. On cooling the 1- [p- Z-amino-ethyl) -benzene-sulfonyl] -2-imino-3-isobutyl-imidazolidine hydrochloride monohydrate, M.P. 151-152 C., crystallizes.
(2) A mixture of ml. dimethyl sulfoxide, 11.2 g. pulverized potassium hydroxide, 23.65 g. p-(Z-aminoethyl)-benzene-sulfonamide-hydrochloride [lit.: E. Miller et al., J. Am. Chem. Soc. 62, 2101 (1940)] and 20.5 g. N-(2-bromine-ethyl) N isobutyl-cyanamide are heated while stirring for 1 hour in an oil bath of After cooling one pours on water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. On cooling and if desired diluting with ether the 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl imidazolidine-dihydrochloride-monohydrate precipitates, M.P. 151-152".
Example 21 39.7 g. l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino- 3-sec.-butyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution which has been dried over sodium sulfate are added 50.5 g. triethyl amine. Thereafter one drops to the solution at room temperature the solution of 12.9 g. valeric acid chloride in 100 ml. methylene chloride within 20 minutes. After stirring the solution for 1 hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted with methylene chloride. The combined methylene chloride phases yield after drying with sodium sulfate, filtrating and evaporating the 1-[p-(2-valer amido ethyl)-phenylsulfonyl]-2- imino-3-sec.-butyl imidazolidine hemihydrate, which melts at ill-113 after recrystallization from ethyl acetate.
In analogous way one obtains from 39.7 g. 1-[p-(2- amino-ethyl)-phenylsulfonyl]-2-imino 3 sec.butyl-imidazolidine-dihydro chloride and:
7.9 g. acetyl chloride the 1-[p-(Z-acetamido-ethyl)-phenylsulfonyl1-2-imino 3 sec.butyl-imidazolidine, M.P. 106-108";
9.2 g. propionyl chloride the 1-[p-(Z-propionamido-ethyl)-phenyl sulfonyl1-2-imino 3 sec.butyl-imidazolidine, M.P.
11 g. butyryl chloride the l-{p-(Z-butyramido-ethyl)- phenylsulfonyl]-2-imino-3-sec.butyl-imidazolidine, M.P.
17.2 g. cyclohexyl-acetyl chloride the 1-[p-(2-cyclohexy1- acetamido ethyl)-phenylsulfonyl] -2-imino-3-sec.butylimidazolidine, M.P. 111-113 18.5 g. p-ethoxybenzoyl chloride the 1-[p-[2-(4-ethoxybenzamido) ethyl] phenylsulfonyl]-2-imino-3-sec.butyl-imidazolidine, M.P. 148-1495";
16.9 g. 2,4-dimethyl benzoyl chloride the 1-[p-[2-(2,4-dimethylbenzamido -ethyl] -phenylsulfonyl] -2-imino-3- sec. butyl-irnidazolidine, M.P. 120-122";
22.8 g. 3-methyl-O-acetyl-salicyclic acid chloride the l-[p- [2-(3-methyl-salicylamido -ethyl] -phenylsulfonyl] -2- imino-3-sec.-butyl-imidazolidine, M.P. 203.5-205";
24.2 g. Z-methoxy-5-tert.butylbutyl-benzoyl chloride the 1- [p- [2- Z-methoxy-S-tert.butyl-benzamido -ethy1) phenylsulfonyl]-2-imino-3-sec.butyl-imidazolidine, M.P. 106-108;
14.8 g. benzoyl chloride the 1-[p-(2-benzamido-ethyl)- phenylsulfonyl]-2-imino-3-sec.butyl-imidazolidine, M.P. 133-135;
(b) The starting material 1- [p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-sec.butyl imidazolidine-dihydrochloride is obtained after two methods for preparation:
1) 36.6 g. 1-[p-(Z-acetamino-ethyl)-phenylsulfonyl]- 2-imino-3-sec.butyl-imidazolidine are dissolved in 370 m. 2 N hydrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuum to dryness and the obtained oil dissolved in ethanol. On cooling the 1-[p-(Z-amino-ethyl)-phenylsulfonyl]-2-imino-3- sec.butyl-imidazolindine-dihydrochloride crystallizes, M.P. 250 (decomposition).
(2) A mixture of 100 ml. dimethyl sulfoxide, 11.2 g. pulverized potassium hydroxide, 23.65 g. p-(2-aminoethyl)-benzene-sulfonamid-hydrochloride [lit.: E. Miller et al., J. Am. Chem. Soc. 62, 2101, (1940)] and 20.5 g. N- (2-bromo-ethyl)-N-sec.butyl-cyanamide is heated while stirring for 1 hour in an oil bath of 110". After cooling one pours on water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. On cooling and if desired diluting with ether the 1-[p-(2-amino-ethyl)- phenylsulfonyl]-2-imino 3 sec.butyl-imidazolidine-dihydrochloride precipitates, M.P. 250 (decomposition).
Example 22 41.5 g. 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino- 3-tert.butyl-imidazolidine-monohydrate are dissolved in 200 ml. water and the base liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution which has been dried over sodium sulfate are added 50.5 g. triethyl amine. Thereafter one drops at room temperature to the solution a solution of 7.9 g. acetyl chloride in 100 ml. methylene chloride within minutes. After stirring the solution for 1 hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylene chloride. The combined methylene chloride phases yield after drying with sodium sulfate, filtrating and evaporating the 1- [p (2 acetamido ethyl) phenylsulfonyl]-2-imino-3- tert.butyl-imidazolidine which melts at 127-129 after recrystallization from ethyl acetate.
Example 23 (a) 41.5 g. 1 [p-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 tert.butyl-irnidazolidine-dihydrochloride-monohydrate are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylene chloride. To the methylene chloride solution which has been dried over sodium sulfate are added 50.5 g. triethyl amine. Thereafter one drops to this solution at room temperature the solution of 13 g. isovaleric acid chloride in 100 ml. methylene chloride Within 20 minutes. After stirring the solution for 1 hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylene chloride. The
combined methylene chloride phases yield after drying with sodium sulfate, filtrating and evaporating the l-[p- (2 isovaleramido-ethyl phenylsulfonyl] 2 imino-3 tert.butyl-imidazolidine which melts at 152-154 after recrystallization from ethyl acetate.
In analogous way one obtains from 41.5 g. 1-[p-(2- amino-ethyl)-phenylsulfonyl] 2 imino 3 tert.butylimidazolidine-dihydrochloride-monohydrate and:
13.0 g. pivaloylchloride the 1-[p-(2-pivalamido-ethyl)- phenylsulfonyl] -2-imino-3 -tert.butyl-imidazolidine, M.P. 140-142;
13.7 g. 2-chlorpropionyl chloride the 1- [p-[2-(2-chlorpropionamido)-ethyl]-phenylsulfonyl]-2-imino-3- tert.butyl-imidazolidine, M.P. 151-153";
15.2 g. 2-chlorbutyryl chloride the l-[p-[2-(2-chlorbutyramido-ethyl phenylsulfonyl] -2-imino-3- tert.butyl-imidazolidine, M.P. 142-144;
15.8 g. cyclohexane-carbonic acid chloride the l- [p-(2- cyclohexane-carboxamido-ethyl -phenylsulfonyl] -2- imino-3-tert.butyl-imidazolidine, M.P. 176-178;
22.5 g. a,u,a-trifluor-m-toluoyl chloride the l-[p-(2- a,a,a-trifluor-m-toluamido-ethyl)-phenylsulfonyl]- 2-imino-3-tert.butyl-imidazolidine, M.P. 172-173";
16.6 g. o-toluoyl chloride the 1-[p-[2-(2-toluarnido)- ethyl] phenylsulfonyl] -2-imino-3-tert.butylimidazolidine, M.P. 160-161";
18.9 g. o-chlorbenzoyl chloride the 1-[p-[2-(2-chlorobenzamido)-ethyl]-phenylsulfonyl]-2-imino-3- tert.butyl-imidazolidine, M.P. 15 2-154;
22.1 g. 2-methoxy-S-chIorine-benzoyl chloride the l-[p- [2-( Z-methoxy-S-chlorob enzamido -ethy1] -pheny1- sulfonyl]-2-imino-3-tert.butyl-imidazolidine, M .P. 124-126";
22.6 g. 3,4-dichlorine-benzoyl chloride the 1- [p-[2-(3,4- dichloro-benzamido -ethyl] -phenylsulfonyl] -2-imino- 3-tert.butyl-imidazolidine, M.P. 168-170;
24.5 g. 3,4,5-trimethoxy benzoyl chloride the 1-[p-[2- (3,4,5-trimethoxybenzamido)-ethyl]-phenylsulfonyl]- 2-imino-3-tert.butyl-imidazolidine, M.P. ISO-132;
18.2 g. 2,5-dimethylbenzoyl chloride the 1-[p-[2-(2,5-
dimethylb en zamido) -ethyl] -phen.ylsulfonyl] -2-imino- 3-tert.butyl-imidazolidine, M.P. 152-154;
11.6 g. butyryl chloride the l-[p-(2-butyramido-ethyl)- phenylsulfonyl]-2-amino-3-tert.butylimidazolidine, M.P. 148-149;
18.0 g. 2-methoxy-benzoyl chloride the 1-[p-[2-(2- methoxybenzamido)-ethyl]-phenylsulfonyl]-2-imino- 3-tert.butyl-imidazolidine, M.P. 131-131.5;
(b) The starting material 1-[p-(Z-amino-ethyl)-phenylsulfonyl] 2 imino 3 tert.butyl imidazolidine dihydrochloride-monohydrate is obtained after two methods for preparation:
(1) 36.65 g. 1-[p-(Z-acetamino-ethyl)-phenylsulfonyl]- 2-imino-3-tert.butyl-imidazoline are dissolved in 370 ml. 2 N hydyrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuum to dryness and the obtained oil dissolved in ethanol. On cooling the l-[p (2 amino-ethyl)-benzenesulfonyl] 2 imino-3- tert.butyl imidazolidine dihydrochloride monohydrate crystallizes, M.P. 232-234.
(2) A mixture of ml. dimethyl sulfoxides, 11.2 g. pulverized potassium hydroxide, 23.65 g. p-(2-amino-ethyl)-phenyl-snlfonamide-hydrochloride [lit.: E. Miller et al., I. Am. Chem. Soc. 62, 2101, (1940)] and 16 g. N-(Z- chloro-ethyl)-N-tert.butyl-cyanamide are heated for 1 hour while stirring in an oil bath of After cooling one pours on water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtratcd and evaporated. The obtained oil (free base) is dissolved in ethanol and made acetic with ethanolic hydrochloric acid. On cooling and if desired diluting with ether the l-[p-amino-ethyl)-phenylsulfonyl]-2-imino- 3 tert.butyl imidazolidine dihydrochloride monohydrate precipitates, M.P. 232-234".
Example 24 40.9 g. 1- [p-(Z-amino-ethyl)-phenylsulfony1] -2-imino-3- cyclopentyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N
. sodium hydroxide. It is extracted with methylene chloride.
To the methylene chloride solution which has been dried over sodium sulfate are added 50.5 g. triethyl amine. Thereafter one drops to the solution at room temperature a solution of 13.0 g. n-valerychloride in 100 ml. methylene chloride within 20 minutes. After stirring the solution for 1 hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylene chloride. The combined methylene chloride phases yield after drying with sodium sulfate, filtrating and evaporating the 1 [p (2 valeramido ethyl) phenylsulfonyl] 2- imino-3-cyclo-pentyl-imidazolidine, which after recrystallization from acetone melts at 132-134.
In analogous way one obtains from 40.9 g. l-[p- (amino ethyl) phenylsulfonyl]-2-imino-3-cyclopentylimidazolidine-dihydrochloride and:
11 g. butyryl chloride the 1-[p-(Z-butyramido-ethyl)- phenylsulfonyl] 2 imino-3-cyclopentyl-imidazolidine, M.P.
14.5 g. n-hexanoyl-chloride the 1-[p-(2-hexanamidoethyl) phenylsulfonyl] 2-imino-3-cyclopentyl-imidazolidine, M.P. 118-110;
15.8 g. cyclohexan carbonic acid chloride the 1-[p-(2- cyclohexan carboxamide ethyl)-phenylsulfonyl]-2- imino-3-cyclopentyl-imidazolidine, M.P. 178-179";
81 g. acetyl chloride the 1 [p (2-acetamido-ethyl)- phenylsulfonyl] 2 imino-3-cyclopentyl-imidazolidine, M.P. 151-162";
18.5 g. 2-chloro-benzoyl chloride the l-[p-[2-(2-chlorobenzamido) ethyl] phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine, M.P. 187-1905";
22.5 g. 2,4-dichloro-benzoyl chloride the 1-[p-[2-(2,4-dichloro-benzamido) ethyl] phenylsulfonyl]-Z-amino- 3-cyclopentyl-imidazolidine, M.P. 15 1.5-15 3 16.5 g. 1-methyl-3-cyclohexene-carbonic acid the 1-[p-[2- (l methyl 3 cyclohexene-carboxamido)-ethyl]- phenylsulfonyl] 2 imino-3-cyclopentyl-imidazolidine, M.P. 129-131";
the 1 [p-[2-(1-methyl-cyclohexancarboxamido)-ethyl]- phenylsulfonyl] 2-imino-3-cyclopentyl-imidazolidine,, M.P. 130-131";
the 1 [p [2-(3-methoxy-benzamido)-ethyl]-phenylsulfonyl] 2 imino-3-cyclopentyl-imidazolidine, M.P. 146.5-148";
the 1 [p [2-(3,4-dimethoxy-benzamido)-ethyl]-phenylsulfonyl] 2 imino-3-cyclopentyl-imidazolidine, M.P. ISO-182;
(b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl] 2 imino-3-cyclopentyl-irnidazolidine-dihydrochloride is obtained after two methods of preparation:
(1) 37.8 g. 1-[p-(2-acetamino-ethyl)phenylsulfonyl]- 2-imino-3-cyclopentyl-imidazolidine are dissolved in 370 ml. 2 N hydrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuum to dryness and the obtained oil dissolved in ethanol. On cooling the 1 [p-(2-amino-ethyl)-benzene-sulf0nyl]-2-imino-3- cyclopentyl-imidazolidine dihydrochloride crystallizes, M.P. 270.
(2) A mixture of 100 ml. dimethyl sulfoxide, 11.2 g. pulverized potassium hydroxide, 23.65 g. p-(2-aminoethyl) phenylsulfonamide-hydrochloride [1it.: E. Miller et al., J. Am. Chem. Soc. 62, 2101, (1940)] and 17.2 g. N (2 chlorine ethyl)-N-cyclopentyl-cyanarnide is heated while stirring for 1 hour in an oil bath of 110 After cooling one pours on water. The obtained cloudy solution is made alkaline with concentrated sodium by droxide, saturated with sodium chloride and extracted three times with methylene chloride; the organic phases are dried over sodium sulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. On cooling and if desired diluting with ether the 1-[p-(2- amino-ethyl)-phenyl-sulfonyl] 2 imino 3 cyclopentyl-imidazolidine-dihydrochloride, M.P. 270" (decomposition) precipitates.
Example 25 (a) 42.3 g. l [p-(Z-amino-ethyl)-phenylsulfonyl]-2- imino 3 cyclohexyl imidazolidine dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried with sodium sulfate 50.5 g. triethylamine are added. To this solution are dropped at room temperature a solution of 9.3 g. propionic acid chloride in ml. methylenechloride within 20 minutes. After stirring the solution for 1 hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylenchloride. The combined methylenchloride phases yield after drying with sodium sulfate, filtrating and evaporating the 1-[p-(2-propionamido-ethyl)-phenylsulfonyl] 2 imino 3-cyclohexylimidazolidine-semihydrate which melts at to 112 if recrystallized from ethyl acetate.
Accordingly one obtains from 42.3 g. 1-[p-(2-aminoethyl) phenylsulfonyl] 2 imino-3-cyclohexyl-imidazolidine-dihydrochloride and:
8.0 g. acetylchloride the l-[p-(2-acetamid0-ethyl)-phenylsulfonyl] 2 imino 3 cyclohexyl-imidazolidine, M.P. 181-183";
10.7 g. butyrylchloride the 1-[p-(Z-butyramido-ethyl)- phenyl-sulfonyl]-2-imino-3-cyclohexyl-imidazolidinehemihydrate, M.P. 143-144;
12.1 g. yalerylchloride the 1-[p-(2-valeramido-ethyl)- phenyl-sulfonyl] -2-imino-3-cyclohexyl-imidazolidine, M.P.154-;
12.1 g. isovalerylchloride the l-[p-(2-isovaleramidoethyl)-phenylsulfonyl]-2-imino-3-cycl0heXy1- imidazolidine, M.P. 180-181 10.5 g. cyclopropane-carboxylic acid chloride the l-[p- (2-cyclopropane-carboxamidoethyl)-pheny1sulfonyl]- 2-imino-3-cyclohexyl-imidazolidine, M.P. 172-173;
18.4 g. 3-cyclohexy1-propionylchloride the 1-[p-[2-(3- cyclohexyl-propionamido -ethyl] -phenylsulfonyl] -2- imino-3-cyclohexyl-imidazolidine, M.P. 168-169";
17.5 g. cinnamic acid chloride the 1-[p-( Z-cinnamicacid-amido-ethyl)-phenylsulfonyl]-2-imino-3- cyclohexyl-imidazolidine, M.P. 182-183";
15.0 g. a-chlorbutyrylchloride the 1-[p-(2-chlorobutyramido-ethyl -phenylsulfonyl] -2-imino-3-cyclohexylimidazolidine, M.P. 158-159";
16.4 g. o-toluylchloride the 1-[p-[2-(2-toluamido-ethyl1- phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine, M.P. 198-199";
18.5 g. o-chlorbenzoylchloride the 1-[p-[2-(2-chlorbenzamido -ethyl] -phenylsulfonyl-2-imino-3-cyclohexylimidazolidine, M.P. 191-192;
18.0 g. o-methoxybenzoylchloride the l-[p-[2-(2-methoxybenzamido-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine, M.P. -176";
18.0 g. m-methoxy-benzoylchloride the 1-[p-[2-(3- methoxy-benzamido-ethyl)-phenylsulfonyl]-2-imino- 3-cyclohexyl-imidazolidine, M.P. 167-168";
17.8 g. 2,S-dimethylbenzoylchloride the 1-[p-[2-(2,5-dimethyl-benzamido)-ethyl]-phenylsulfonyl]-2-imino-3- cyclohexyl-imidazolidine, M.P. 186-187";
19.4 g. p-ethoxy-benzoylchloride the 1-[p-[2-(4-ethoxy- 'b enzamidoyethyl]-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine, M.P. 156-1575";
23.0 g. o-brombenzoylchloride the 1-[p-[2-(2-brombenzamido) -ethyl] -phenylsulfonyl] -2-imino-3-cyclohexylimidazolidine, M.P. 179-181";
15.0 g. Z-ethyI-butyrylchloride the l-[p-[2-(2-ethyl-butyramido) -ethyl] -phenylsulfonyl] -2-imino-3 -cyclohexylimidazolidine, M.P. 169-170;
17.5 g. 3-cyclohexyl-propionylchloride the 1-[p-[2-(2- cyclohexyl-propionamido -ethyl] -phenylsulfonyl] -2- imino-3-cyclohexyl-imidazolidine, M.P. 168-169";
18.2 g. p-methoxy-benzoylchloride the 1-[p-[2- (4- methoxy-benzamido) -ethyl] -phenylsulfonyl] -2-imino- 3-cyclohexylimidazolidine, M.P. 153-l54;
19.1 g. 2-methylthio-benzoylchloride the l-[p-[2-(methylthio-benzamido -ethyl -phenylsulfonyl -2-imino-3 cyclohexyl-imidazolidine, M.P. 184-186";
21.5 g. 3,4-dichlor-benzoylchloride the 1-[p-[2-(3.4-dichlorobenzamido) -ethyl] -phenylsulfonyl -2-imino-3- cyclohexyl-imidazolidine, M.P. 227-228";
21.0 g. Z-methoxy-S-chlorobenzoylchloride the 1-[p-[2- (Z-methoxy-S-chlorobenzamido)-ethyl]-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine,
16.5 g. 1-methyl-3-cyclohexene-carbonic acid chloride the 1-[p-[2-(1-methyl-3-cyclohexene-carboxamido)- ethyl]-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine, M.P. l58-l60;
16.5 g. 4-methyl-3-cyclol1exene-carbonic acid chloride the 1-[p-[2-(4methyl-3-cyclohexene-carboxamido)- ethyl] -phenylsulfonyl] -2-imino-3 -cyclohexylimidazolidine, M.P. 200-201";
15.0 g. cyclohexane carbonic acid chloride the 1-[p-(2- cyclohexane-carboxamido-ethyl) -phenylsultonyl] -2- imino-3-cyclohexyl-imidazolidine, M.P. 208209;
16.3 g. 1-methy1-cyclohexane-carbonic acid chloride the 1- [p- [2- 1-rnethyl-cyclohexane-carboxarnido -ethyl 1 phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine, M.P. 162-163; I
the 1- [p- [2- 3,4-dimethoxy-benzamido -ethyl] -phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine, M.P. 203-2S0;
(b) The starting material 1-[p-(2-amino-ethyl)-pheny1- sulfonyl] 2 imino-3-cyclol1exyl-imidazolidine-dihydrochloride is prepared according two different methods:
(a) 39.2 g. 1-[p-(2-acetamino-ethyl)-phenylsulfonyl]- 2-imino-3-cyclohexyl-imidazolidine are dissolved in 370 ml. 2 N hydrochloric acid and the solution is refluxed for 6 hours. The solution is evaporated in vacuo and the oil obtained dissolved in ethanol. On cooling the l-[p- (2 amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexylimidazolidine-dihydrochloride crystallizes M.P. 247-250".
(b) A mixture of 100 ml. dimethylsulfoxide, 11.2 g. pulverized potassium hydroxide, 23.65 g. p-(Z-aminoethyl)benzene-sulfonamide hydrochloride [Lit.: E. Miller et al., J. Am. Chem. Soc. 62, 2101, (1940)] and 23.1 g. N (2 brom-ethyl)-N-cyclohexyl-cyanamide are heated while stirring for 1 hour in an oil bath of 110. After cooling one pours on water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and three times extracted with methylenchloride; the organic phases are dried over sodium sulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acidic with saturated hydrochloric acid in ethanol. On cooling and if desired diluting with ether the 1-[p-(2-amino-ethyl)- phenylsulfonyl] 2 imino 3 cyclohexyl-imidazolidinedihydrochloride, M.P. 247-250 precipitates.
Example 26 (a) According Example 25(a) one obtains from 43.7 g. 1 [p-amino-ethyl)-phenylsulfonyl]-2-imino-3-cycloheptyl-imidazolidine-dihydrochloride and 7.9 g. acetylchloride the 1 [p-(Z-acetamido-ethyl)-phenyl-sulfonyl]- 2-imino-3-cycloheptyl-imidazolidine, M.P. 166-167.
From the same amino compound one obtains from:
11.0 g. butyrylchloride the 1-[p-(Z-butyramido-ethyD- phenylsulfonyl] -2-imino-3 -cycloheptyl-imidazolidine, M P
(b) The starting material 1-[p-(amino-ethyl)-phenylsulfonyl] 2 imino-B-cycloheptyl-imidazolidine-dihydrochloride is prepared according Example 25 (b) from 40.6 g. 1 [p-(2-acetamino-ethyl)-phenylsulfonyl]-2-imino-3- cycloheptyl-imidazolidine-dihydrochloride, M.P. 280 (decomposition).
Example 27 (a) 41.1 g. 1-[p-(3-amino-propyl)-phenylsulfonyl]-2- imino-3-butyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. Thereafter one drops to this solution at room temperature the solution of 13 g. isovalerylchloride in ml. methylenchloride within 20 minutes. After the solution has been stirred for 1 hour at room tempearture it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylchloride. The combined methylenchloride phases yield after drying with sodium sulfate, filtrating and evaporating the 1 [P-(3 isovaleramido-propyl)-phenyl-sulfonyl]-2-irnino-3-butyl-imidazolidine which melts at 101- 103 if recrystallized from ethyl acetate.
In analogous method one obtains from 41.1 g. 1-[p-(3- aminopropyl) -phenylsulfonyl] -2-imino-3-butyl-imidazolidine and:
22.0 g. 2-methoxy-S-chlorobenzoylchloride the 1-[p-2-(2- methoxy-S-chlorobenzamido -propyl] -phenylsulfonyl] 2-imino-3-butyl-imidazolidine as oil.
18.2 g. 3,5-dimethyl-benzoylchloride the 1-[p-(3,5-dimethyl-benzamido)-propyl]-phenylsulfonyl] 2-imino-3-bu tyl-imidazolidine, M.P. 96-100".
The starting material 1- [p-(3-amino-propyl)-pheny1sulfonyl]-2-imino-3-butyl-imidazolidine-dihydrochloride can be obtained according two different methods:
(a) 38.0 g. 1-[p-(3 acetamino-propyl)-phenylsulfonyl]-2-imino-3-butyl-imidazolidine are dissolved in 370 ml. 2 N hydrochloride acid and the solution is refluxed for 6 hours. The solution is evaporated in vacuo to dryness and the oil obtained is dissolved in ethanol. On cooling the 1-[p-(3-amino-propyl)-phenylsulfonyl]-2-imino-3- butyl-imidazolidine-dihydrochloride crystallizes as very hydroscopic crystals.
(b) A mixture of 100 ml. dimethylsulfoxide, 11.2 g. pulverized potassium hydroxide, 250 g. p-(3-aminopropyl) benzene sulfonamide hydrochloride[Lit.: E. Miiller, Agnew. Chemie, 61, 179, (1949)] and 16 g. N- (2-chlor-ethyl)-N-butyl-cyanamide is heated for 1 hour in an oil bath of while stirring. After cooling one pours on water. The obtained cloudly solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted with methylenchloride three times; the organic phases are dried over sodium sulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. On cooling and if desired dilution with ether the 1-[p-(3-amino-propyl)- phenylsulfonyl] 2 imino-3-butyl-imidazolidine-dihydrochloride precipitates as very hygroscopic crystals.
Example 28 (a) 41.1 g. 1-[p-(3-amino-propyl)-phenylsu1fonyl]-2- imino 3-isobuty1-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. To this solution is dropped at room temperature a solution of 13 g. pivaloyl-chloride in 100 ml. methylenchloride within 20 minutes. After the solution has been stirred at room temperature for 1 hour it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylenchloride. The combined methylenchloride phases yield after drying With sodium sulfate, filtrating and evaporating the l-[p- (3 pivalamido-propyl)-pheny1sulfonyl]-2-imino-3-isobutyl-imidazolidine which melts after recrystallization from ethyl acetate at 112113 (b) The starting material 1-[p-(3-amino-propyl)-phenylsulfonyl] -2-imino-3-isobutyl-imidazolidine-dihydrochloride can be obtained according two methods:
(a) 38.0 g. 1-[p-(S-acetamino-propyl)-phenylsulfonyl]- 2-imino-3-isobutyl-imidazolidine are dissolved in 370 ml. 2 N hydrochloric acid and the solution is refluxed for 6 hours. The solution is evaporated in vacuo and the oil obtained the 1 [p-(3-aminopropyl)-phenylsulfonyl]-2- imino 3 isobutyl-imidazolidine-dihydrochloride used crudely.
(b) A mixture of 100 ml. dimethylsulfoxide, 11.2 g. pulverized potassium hydroxide, 25.0 g. p-(3-aminopropyl) benzene sulfonamide hydrochloride [Lit.: E. Miiller, Agnew. Chemie, 61, 179, (1949)] and 20.5 g. N- (2 brom-ethyl)N-isobutyl-cyanamide is heated while stirring for 1 hour in an oil bath of 110. After cooling one pours on water. The obtained cloudy solution is extracted with concentrated sodium hydroxide; the organic phases are dried over sodium sulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. After evaporating one obtains the 1-[p-(3-aminopropyl)-phenylsulfonyl]-2-imino-3-isobuty1-imidazolidine dihydrochloride as an oil.
Example 29 41.1 g. 1-[p-(3-amino-propyl)-phenylsulfonyl]-2-imino- 3 tert.-butyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. To this solution is dropped at room temperature the solution of 18.2 g. 3,4-dimethyl-benzoylchloride in 100 ml. methylenchloride within 20 minutes. After the solution has been stirred for 1 hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylenchloride. The combined methylenchloride phases yield after drying with sodium sulfate, filtrating and evaporating the 1-[p-(3,4-dimethylbenzamido)- propyl) phenylsulfonyl] 2-imino-3-tert.butyl-imidazolidine which melts after recrystallizing from ethyl acetate at 144-146".
(b) The starting material 1-[p-(3-amino-propyl)-phenylsulfonyl] 2 imino-3-tertbutyl-imidazolidine-dihydrochloride is obtained according two methods:
(1) 38.0 g. 1 [p (3 acetamino-propyl)-phenylsulfonyl] 2 imino-3-tert.butyl-imidazolidine are dissolved in 370 m1. 2 N hydrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuo to dryness and the oil obtained the 1-[p-(3-amino- 28 propyl)benzene-sulfonyl] 2-imino-3-tert.butyl-imidazolidine-dihydrochloride used crudely.
(2) A mixture of m1. dimethylsulfoxide, 11.2 g. pulverized potassium hydroxide, 25.0 g. p-(3 aminopropyl)-benzene sulfonamide hydrochloride [lit.: E. Miiller, Angew. Chem, 61, 179, (1949)] and 16 g. N-(2- chloro ethyl) N tert.butyl cyanamide is heated while stirring for 1 hour in an oil bath of After cooling one pours on water. The obtained cloudy solution is made alkaline with concentrated sodium hydroxide, saturated with sodium chloride and extracted three times with methylenchloride. The organic phases are dried over sodium sulfate, filtrated and evaporated. The obtained oil (free base) is dissolved in ethanol and made acidic with saturated ethanolic hydrochloric acid. After evaporating one obtains the l-[p-(3-amino-propyl)-phenylsulfonyl] 2 imino 3 tert.butyl imidazolidinedihydrochloride as an oil.
Example 30 (a) 41.1 g. 1-[p-(2 amino-ethyl)-phenylsulfonyl]-2 imino 3 butyl 4 methyl-imidazolidine-dihydrochloride are dissolved in 200 ml. water and the base is liberated with 300 ml. 2 N-sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried over sodium sulfate are added 50.5 g. triethylamine. To this solution is dropped at room temperature the solution of 12.7 g. valeryl chloride in 100 ml. methylenchloride within 20 minutes. After the solution has been stirred at room temperature for 1 hour it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylenchloride. The combined methylenchloride phases yield after drying with sodium sulfate, filtrating and evaporating the 1-[p-(2-valeramidoethyl) phenylsulfonyl] 2 imino 3 butyl 4 methylimidazolidine which melts after recrystallization from ethyl acetate at 108-110".
Accordingly one obtains from 41.1 g. 1-[p-(2-amino ethyl)-phenylsulfonyl] 2 imino 3 butyl-4-methylimidazolidine-dihydrochloride and:
12.7 g. isovalerylchloride the 1 [p-(2 isovaleramidoethyl)-phenylsulfonyl] 2 imino 3 butyl-4-methylimidazolidine, M.P. 102-403";
15.4 g. cyclohexane-carboxylic chloride the 1-[p-(2-cyclohexan-carboxamido-ethyl)-phenylsulfony1] 2 imino- 3-butyl-4-methyl-imidazolidine, M.P. 137-139;
16.3 g. o-toluoylchloride the 1-[p-[2-(2-toluamido)-ethyl]- phenylsulfonyl] 2 imino 3 butyl 4 methyl-imidazolidine-hemihydrate, M.P. 103-105 23.7 g. o-bromobenzoylchloride the 1-[p-[2 (2 brombenzamido)-ethyl]-phenylsulfonyl] 2 imino-3-butyl- 4-methyl-imidazolidine, M.P. 100-102";
18.0 g. 3,5 -dimethyl benzoylchloride the 1-[p-[2-(3,5- dimethyl benzamido) ethyl] phenylsulfonyl] 2- imino-3-butyl-4-methyl-imidaz0lidine, M.P. 138140;
7.9 g. acetylchloride the 1 [p (2 acetamido-ethyl)- phenyl-sulfonyl] 2 imino 3 butyl 4 methylimidazolidine, M.P. 132133;
18.2 g. 2,4 dimethyl-benzoylchloride the 1-[p-[2-(2,4- dimethyl benzamido) ethyl] phenylsulfonyl] 2- imino 3 butyl 4 methyl-imidazolidine- AtH O, M.P. 108110;
(b) The starting material 1- [p-(Z-amino-ethyl)-phenylsulfonyl] 2 imino 3 butyl 4 methyl-imidazolidinedihydrochloride is, prepared according the following method:
38.0 g. 1-[p (2 acetamino-ethyl)-phenylsulfonyl]-2- imino 3 butyl 4 methyl-imidazolidine are dissolved in 370 ml. 2 N hydrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuo to dryness and the oil obtained dissolved in alcohol. On cooling the 1-[p-(amino-ethyl)-phenylsulfonyl]- 2-imino 3 butyl 4 methyl-imidazolidine-dihydrochloride crystallizes, M.P. 240 (decomposition).
Example 31 (a) According Example 30 (a) one obtains from 41.1 g. 1-[p-(2 amino-ethyl)-phenylsulfonyl] 2 imino-3- butyl-S-methyl-imidazolidine and:
7.9 g. acetylchloride the l-[p-(2-acetamid0-ethyl)-pheny1- sulfonyl] 2 imino 3 butyl-5-methyl-imidazolidine, M.P. 98-99";
12.5 g. valerylchloride the 1-[p-(2 valeramido-ethyD- phenyl-sulfonyl] 2 imino 3 butyl-5-methylimidazolidine, M.P. 95-97;
12.5 g. isovalerylchloride the 1 [p-(2 isovaleramidoethyl)-phenylsulfonyl] 2 imino 3 butyl-S-methylimidazolidine, M.P. 131-133";
14.1 g. 2 ethyl-butyrylchloride the 1-[p-[2 (2 ethylbutyramido)-ethyl]-phenylsulfonyl] 2 imino-3-butyl- S-methyl-imidazolidine, M.P. 89-90";
16.5 g. 2 toluoylchloride the 1- [p-[2 (2 toluamido)- ethyl]-phenylsulfonyl] 2 imino 3 butyl-S-methylimidazolidine, M.P. 122-124;
22.0 g. 2 brombenzoylchloride the 1-[p-(2 brombenzamido ethyl) phenylsulfonyl] 2 imino-3-butyl-5- methyl-imidazolidine, M.P. 105-107";
15.5 g. cyclohexane carboxylic chloride the 1 [p [2- (cyclohexane-carboxamido) ethyl] phenylsulfonyl1- 2-imino 3 butyl 5 methyl-imidazolidine, M.P. 127- 129.
(b) The starting material 1 [p-(2 amino-ethyl)- phenylsulfonyl] 2 imino 3 butyl 5 methyl-imidazolidine-dihydrochloride is prepared according Example 29 (b) from 38.0 g. l-[p-(Z acetamino-ethyl)-phenylsulfonyl] 2 imino 3 butyl 5 methyl-imidazolidinedihydrochloride, M.P. 255-257".
Example 32 (a) According Example 30 (a) one obtains from 43.7 g. 1 [p (2 amino ethyl) phenylsulfonylJ-Z-imino- 3 cyclohexyl 5 methyl-imidazolidine-dihydrochloride and 10.7 g. butyrylchloride the l-[p-(2-butyramido-ethyl)- phenylsulfonyl] 2 imino 3 cyclohexyl 5 methylimidazolidine, M.P. 109-111".
(b) The starting material 1 [p (2 amino-ethyl)- phenylsulfonyl] 2 imino 3 cyclohexyl 5 methylimidazolidine dihydrochloride is obtained according Example 29 (b) from 40.6 g. 1-[p-(2 acetamino-ethyl)- phenylsulfonyl] 2 imino 3 cyclohexyl 5 methylimidazolidine-dihydrochloride as oil.
Example 33 42.5 g. 1 [p (2 amino-ethyl)-phenylsulfonyl] 2- imino 3 butyl 4 ethyl-imidazolidine-dihydrochloride are dissolved in 300 ml. water and the base is liberated with 300 ml. 2 N sodium hydroxide. It is extracted with methylenchloride. To the methylenchloride solution which has been dried with sodium sulfate are added 50.5 g. triethylamine. To this solution is dropped at room temperature the solution of 13 g. valeryl-chloride in 100 ml. methylenchloride within 20 minutes. After the solution has been stirred for one hour at room temperature it is washed with 100 ml. 2 N sodium hydroxide and twice with 100 ml. water. The aqueous phases are extracted twice with methylenchloride. The combined methylenchloride phases yield after drying with sodium sulfate, filtrating and evaporating the l-[p-(2valeramido-ethyl)-phenylsulfonyl] 2 imino 3 butyl 4 ethyl-imidazolidine recrystallized from ether/ ethyl acetate, it melts at 92-94.
In analogous way one obtains from 42.5 g. 1-[p-(2- amino ethyl) phenylsulfonyl]-2-imino-3-butyl-4-ethylimidazolidine-dihydrochloride and:
11.5 g. isobutyrylchloride the 1-[p-(2-isobutyramidoethyD-phenylsulfonyl]-2-imino-3-butyl-4-ethylimidazolidine as an oil;
13.0 g. pivaloylchloride the 1-[p-(2-pivalamido-ethyl)- phenyl-sulfonyl] -2-imino-3-butyl-4-ethylimidazolidine, M.P. 140-142;
15.2 g. 2-chlorobutyrylchloride the 1-[p-[2-(2-chlorbutyramido -ethyl] -phenylsulfonyl] -2-imino- '3-butyl-4-ethyl-imidazolidine as an oil;
22.6 g. 2,S-dichlorobenzoylchloride the 1-[p-[2-(2,5- dichlorbenzamido-ethyl) -phenylsulfonyl] -2-imino- 3-butyl-4-ethyl-irnidazolidine as an oil.
(b) The starting material 1-[(2-amino-ethyl)-phenyl sulfonyl] 2-imino-3-butyl-4-ethyl-imidazolidine-dihydrochloride is obtained according to the following method:
39.4 g. 1 [p (2 acetamino-ethyl)-phenylsulfonyl]-2 imino-3-buty1-4-ethyl-imidazolidine are dissolved in 370 ml. 2 N hydrochloric acid and the solution is refluxed for 6 hours. The solution is evaporated in vacuo to dryness and the oil obtained dissolved in ethanol. 0n cooling the 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino 3 butyl 4 ethyl imidazolidine dihydrochloride crystallizes, M.P. 222-224".
Example 34 28 ml. 4 N sodium hydroxide and 4.3 g. ethylenimine are cooled to -10. To this solution is then added a suspension of 26.2 g. p-(Z-acetamidoethyl)-phenylsulfochloride in ml. acetone while stirring and cooling so that the temperature does not rise above 0. After adding is finished stirring is continued for 30 minutes at 0. Thereafter the cooling bath is removed and to the solution of the obtained 1-[p-(2-acetamido-ethyl)-phenylsulfonyl]-aziridine are added 100 ml. n-propylamine. The temperature rises to 40-50. The reaction mixture is stirred for another hour and finally the excess of amine is distilled off on the rotary evaporator. The crystalline paste containing beside sodium chloride the desired N [p-(2-acetamido-ethyl)-phenylsulfonyl]-N -n-propyl-ethylendiamine is dissolved in 5 6 ml. 2 N sodium hydroxide and to this solution is added portionwise while stirring 10.6 g. bromcyan whereby the temperature is not allowed to rise above 40. After 1 hour the obtained compound is extracted with methylenchloride, washed with 20 ml. 2 N sodium hydroxide and twice with 100 ml. water. After drying and evaporating of the methylenchloride solution the residue is recrystallized from ethyl acetate and yields the I-[p-(Z-acetamidoethyl) phenylsulfonyl]-2-imino-3-n-propyl-irnidazolidine, M.P. 138-140.
Example 35 reaction mixture is stirred for another hour and thereafter the excess of amine is distilled 01f on the rotary evaporator. The crystalline paste which contains beside sodium chloride the desired N [p( 2-propionamido-ethyl) -phenylsulfonyl]=N -n-propyl-ethylendiamine is dissolved in 66 ml. 2 N-sodium hydroxide and to this solution are added portionwise while stirring 10.6 g. bromcyan whereby the temperature is not allowed to rise above 40. After 1 hour the obtained compound is extracted with methylenchloride, washed with 20 ml. 2 N sodium hydroxide and twise with 100 ml. water. After drying and evaporating of the methylenchloride solution the residue is recrystallized from ethyl acetate and yields the 1-[p-(2-propionamide-ethyl)-phenylsulfonyl] 2 imin0-3-n-propyl-imid- 31 chloride the 1-[(2-butyramido-ethyl) phenylsulfonyl]-2- imino-3-propyl-imidazolidine, M.P. 114-116".
Example 36 28 ml. 4 N sodium hydroxide and 4.3 g. ethylenimine 5 are cooled to --10. Thereafter a suspension of 35.5 g. p- [2- 2-methoxybenzamido) -ethyl] -phenylsulfochloride in 100 ml. acetone while stirring and cooling is added so that the temperature does not rise above After dropping to is finished stirring is continued for '30 minutes at 0. Thereafter the cooling bath is removed and to the solution of the obtained [2-(2-methoxy-benzamido-ethyl)-phenylsulfonyll-aziridine are added 100 ml. n-propylamine. The temperature rises to 40-50. The reaction mixture is stirred for another hour and thereafter the excess of amine is dis tilled off on the rotary evaporator. The crystalline paste which contains beside sodium chloride the desired N [p- [2-(2-methoxy-henzamido) ethyl] phenylsulfonyl]-N n-propyl-ethylendiamine is dissolved in 56 ml. 2 'N sodium hydroxide and to this solution is added while stirring portionwise 10.6 g. bromcyan whereby the temperature does not rise above 40. After 1 hour the obtained compound is extracted with methylenchloride, washed with 20 ml. 2 N sodium hydroxide and twice with 100 ml. Water. After drying and evaporating of the methylenchloride solution the residue is recrystallized from ethyl acetate and yields the 1-[p-[2-(2-methoxy benzamido)-ethyl]- phenylsulfonyl]-2-imino-3-n-propyl imidazolidine, M.P.
In analogous manner one obtains from 4.3 g. ethylenimine and:
100 ml. isopropylamine and 26.2 g. p-(2-acetamido-ethyl)- phenylsulfochloride the 1-[p-(2 acetamido ethyl)- phenylsulfonyl-2-imino-3-isopropyl-imidazolidine, M.P. 133-135;
100 ml. isopropylamine and 27.6 g. p-(propionamidoethyl) phenylsulfochloride the 1 [p (2 propionamido-ethyl) phenylsulfonyl] 2 imino-3-isopropylimidazolidine, M.P. Ill-112;
100 ml. isopropylamine and 29 g. p-(2-butyramido-ethyl)- phenylsulfochloride the l-[p-(Z butyramido ethyl) phenylsulfonyl]-Z-imino 3 isopropyl imidazolidine, M.P. 139140;
100 ml. butylamine and 26.2 g. p-(2-acetamido-ethyl)- phenylsulfochloride the 1 [p (2 acetamido-ethyl)- phenylsulfonyl]-2-imino 3 butyl-imidazolidine, M.P.
100 ml. butylamine and 30.6 g. [Z-(a-methyI-butyramido)-ethyl]-phenylsulfochloride the 1-[p-[2-(a-methy1- butyramido)-ethyl] phenylsulfonyl] 2 imino-3-nbutyl-imidazolidine, M.P. 114-116;
100 ml. butylamine and 30.6 g. p-(2-valeramido-ethyl)- phenylsulfochloride the 1-[p-(2-valeramido-ethyl)- phenylsulfonyl]-2-imino-3-butyl imidazolidine, M.P. 130;
100 ml. isobutylamine and 30.6 g. p-(2-valeramido-ethyl)- phenylsulfochloride the 1 [p (2 valera-mido-ethy1)- phenylsulfonyl] 2 imino 3 isobutyl-imidazolidine, M.P. 137-140";
100 ml. isobutylamine and 38.9 g. p-[2-(2-methoxy-5- chlor-benzamido)-ethyl]-phenylsulfochloride the l-[p- [2 methoxy chlor-benzamido)-ethyl]-phenylsulfonyl]-2-imin0-3-isobutylimidazolidine, M.P. 117-119 100 ml. isobutylamine and 33.0 g. p-(2-cyclohexane-car boxamido-ethyl)-phenylsulfochloride the l-[p-(2-cyclohexane-carboxamido-ethyl)-phenylsulfonyl] 2 imin0-3-isobutyl-imidazo1idine, M.P. 175177;
100 ml. sec. butylamine and 26.2 g. p-(2-acetamido-ethyl) -phenylsulfochloride the 1- [p- (Z-acetamido-ethyl) phenylsulfonyl] -2-imino-3-sec.butyl-imidazolidine, M.P.
100 ml. sec.butylamine and 27.6 g. p-(2-propionamidoethyl)-phenylsulfochloride the 1-[p-(2-propionamido- 32 ethyl)-phenylsulfonyl] 2 imino-3-sec-butyl-imidazolidine, M.P.
ml. sec.butylamine and 29.0 g. p-(2-butyramidoethyl)-phenylsulfochloride the 1-[p-(2-butyramido-ethyl)-phenylsulfonyl]-2-imino 3 sec.butyl-imidazolidine, M.P.
100 ml. tert.butylamine and 26.2 g. p-(2-acetamido-ethyl)- phenylsulfochloride the 1-[p-(2-acetamido-ethyl)-phenylsulfonyl]-2-imino 3 tert.butyl-imidazolidine, M.P. 127-128";
100 ml. tert.butylamine and 27.6 g. p-(Z-propionamidoethyl)-phenylsulfochl0ride the 1-[p(2-propionamidoethyl)-phenylsulfochloride the 1-[p-(2-propi0namid0- ethyl) phenylsulfonyl]-2-imino-3-tert.butyl-imidazolidine, M.P. ISO-152.
Example 37 28 ml. 4 N sodium hydroxide and 4.3 g. ethylenimine are cooled to 10. Thereafter a suspension of 29.0 g. p-(2-butyryl-an1ido-ethyl)-phenylsulfochloride in 100 ml. acetone is added while stirring and cooling so that the temperature does not rise above 0". After dropping to is finished it is stirred for another 30 minutes at 0. Thereafter the cooling bath is removed and to the solution of the obtained 1-[p-(Z-butyramido-ethyl)-phenylsu1fonyl]-aziridine are added 100 m1. tert.butylamine. The temperature rises to 40-50. The reaction mixture is stirred for another hour and thereafter the excess of amine is distilled off on the rotary evaporator. The crystalline paste which contains besides sodium chloride the desired N -[p-(2-butyramido-ethyl)-phenylsulfonyl] N tert. butylethylendiamine is dissolved in 56 ml. 2 N sodium hydroxide and to this solution are added while stirring portionwise 10.6 g. bromocyan whereby the temperature is not allowed to rise above 40. After 1 hour the obtained compound is extracted with methylenchloride, washed with 20 ml. 2 N sodium hydroxide and twice with 100 ml. water. After drying and evaporating of the methylenchloride solution the residue is recrystallized from ethyl acetate and yields the 1-[p-(2-butyramido-ethyl)- phenylsulfonyl]-2-imino-3-tert.butyl-imidazolidine, M.P. 148-149.
In analogous ways one obtains from 4.3 g. ethylenimine and:
100 ml. tert.butylamine and 30.6 g. p(2-a-methy1butyramido-ethyl)-phenylsulfochloride the l-[p-(2-a-methylbutyrarnido-ethyl)-phenylsulfonyl] 2 imino-3-tert. butyl-imidazolidine, M.P. 156-157";
100 ml. tert.butylamine and 30.6 g. p-(2-isovaleramidoethyl)-phenylsulfochloride the 1-[p-(2-isovaleramidoethyD-phenylsulfonyl]-2-imino 3 tert.buty1-imidazolidine, M.P. 152-154";
100 ml. tert.buty1amine and 35.5 g. p-[2-(2-methoxybenzamido -ethyl] -phenylsu1foch1oride the 1- [p [2- 2-methoxybenzamido)-ethyl]-phenylsulfonyl] 2 imino-3- tert.butyl-imidazo1idine, M.P. 134-136";
100 ml. tert.butylamine and 39.0 g. p-[2-(2-methoxy-5- chlorobenzamido) -ethyl] -phenylsulfochloride the 1- [p- [2-(2-methoxy 5 chlor0benzamide)-ethyl]-phenylsulfonyl]-2-imino-3-tert.butyl-imidazolidine, M.P. 124- 126;
100 ml. cyclopentylamine and 30.6 g. p(2-valeramidoethyl)-phenylsulfochloride the l-[p-(2-valeramido-ethyl)-phenylsulfonyl] 2 imino 3 cyclopentyl-imidazoline, M.P. 132-134;
100 ml. cyclopentylamine and 29.0 g. p-(2-butyramidoethyl)-phenylsulfochloride the 1-[p-(2-butyramido-ethyl)-phenylsulfonyl] 2 imino 3 cyclopentyl-imidazolidine, M.P.
100 ml. cyclopentylamine and 33.0 g. p-(2-cyclohexanecar-boxamido-ethyl)-phenylsulfochloride the 1-[p-(2- cyclohexane-carboxamido-ethyl) phenylsulfonyl] 2- imino-3-cyclopentyl-imidazolidine, M.P. 178-179;
100 ml. cyclohexylamine and 24.8 g. p-(2-formamidoethyl)-phenylsulfochloride the 1-[p-2-formamido-ethyl)- 3B phenylsulfonyl] 2 imino 3 cyclohexylimidazlidine, M.P. 135-136;
100 ml. cyclohexylamine and 26.2 g. p-(Z-acetamidoethyl)-phenylsulfochloride the I-[p-(Z-acetamido-ethyl)-phenylsulfonyl 2 imino-3-cyclohexyl-imidazolidine, M.P. 181-183;
100 ml. cyclohexylamine and 29.0 g. p-[2-N-methylacetamido)-propyl]-phenylsulfochloride the 1 [PlZ-(N- methyl-acetamido)-propyl]-phenylsulfonyl] 2 imino- 3-cyclohexyl-imidazolidine, M.P. 108-110;
100 ml. cyclohexylamine and 27.6 g. p-(Z-propionamidoethyl)-phenylsulfochloride the l-[p-(Z-propionarnidoethyl) phenylsulfonyl] 2 imino 3 cyclohexylimidazolidine- /z H O, M.P. 110-112";
100 ml. cyclohexylamine and 29.0 g. p-(Z-butyramidoethyl)-phenylsulfochloride the l-[p-(2 butyramido-ethyl)-phenylsulfonyl]-2-imino 3 cyclohexyl-imidazolidine-V2 H O, M.P. 143-144;
100 ml. cyclohexylamine and 30.4 g. p-(2-valeramido-ethyl -phenylsulfochloride the 1- [p- (2-valeramido-ethyl) phenylsulfonyl] 2 imino 3 cyclohexyl-imidazolidine- A H O, M.P. 154-155;
100 ml. cyclohexylamine and 30.4 g. p-(2-isovaleramidoethyl)-phenylsulfochloride the 1-[p-(2-isovaleramidoethyD-phenylsulfonyl] 2 imino 3 cyclohexylimidazolidine, M.P. 180-181;
100 ml. cyclohexylamine and 35.4 g. p-[2-(2-methoxybenzamido)-ethyl]-pheny1sulfochloride the 1-[p-[2-(2- methoxy-benzamido)-ethyl]-phenylsulfonyl] Z-imino- 3-cyclohexyl-imidazolidine, M.P. 105-107";
100 ml. cyclohexylamine and 33.0 g. p-(Z-cyclohexyl-carboxamido-ethyl) -phenylsulfochloride the 1- [p-(Z-cyclohexyl-carboxamido-ethyl) phenylsulfonyl] 2 imino- 3-cyclohexyl-imidazolidine, M.P. 167-168";
100 ml. cycloheptylamine and 26.2 g. p-(Z-acetamidoethyl)-phenylsulfochloride the l-[p-(Z-acetamido-ethyl)-phenylsulfonyl] 2 imino-3-cyc1oheptyl-imidazolidine, M.P. 166-167;
100 ml. cycloheptylamine and 29.0 g. p-(2-butyramidoethyl)-phenylsulfochloride the 1- [p-(2-butyramido-ethyl)-phenylsulfonyl]-2-imino 3 cycloheptyl-imidazolidine, M.P.
Example 38 28 ml. 4 N sodium hydroxide and 5,7 g. propylenimine are cooled to Thereafter a suspension of 29.0 g. p- (2-butyramido-ethyl)-phenylsulfochloride in 100 ml. acetone is added while stirring and cooling so that the temperature does not rise above 0. After dropping to is finished the reaction mixture is stirred for 30 minutes at 0". Then the cooling bath is removed and to the solution of the obtained 1- [p-(butyramido-ethyl)-phenylsulfonyl]- Z-methyl-aziridine are added 100 ml. cyclohexylamine. The temperature rises to 40-50. The reaction mixture is stirred for 1 hour and thereafter the excess of amine is distilled off on the rotary evaporator. The crystalline paste which contains besides sodium chloride the desired 2-[p-(2 butyramido-ethyl)-phenylsulfonyl] 1 cyclohexylamino-propane is dissolved in 56 ml. 2 N sodiumhydroxide and to this solution is added while stirring portion wise 10.6 g. brom/cyan whereby the temperature is not allowed to rise above 40. After 1 hour the obtained compound is extracted with methylenchloride, washed with 20 ml. 2 N sodium hydroxide and twice with 100 ml. water. After drying and evaporating of the methylenchloride solution the residue is recrystallized from ethyl acetate and yields the l-[p acetamido ethyl)-phenyl sulfonyl] 2 imino-3-cyclohexyl-S-methyl-imidazolidine, M.P. 109-111.
Example 39 28 ml. 4 N sodium hydroxide and 5.7 g. propylenimine are, cooled to l0. Thereafter a suspension of 26.2 g. p-(2-acetamidoethyl)-phenylsulfochloride in 100 ml. acetone is added while stirring and cooling so that the temperature does not rise above 0. After dropping to is finished the reaction mixture is stirred for 30 minutes at 0". Then the cooling bath is removed and to the solution of the obtained l-[p (2 acetamido-ethyl)-phenylsulfonyl] 2 methyl aziridine are added ml. n-butylamine. The temperature rises to 40-50. The reaction mixture is stirred for 1 hour and thereafter the excess of amine is distilled off on the rotary evaporator. The crystalline paste which contains besides sodium chloride the desired 2 [p-( acetamido-ethyl)-phenylsulfonyl]-1-nbutylamino-propane is dissolved in 56 ml. 2 N sodium hydroxide and to this solution is added while stirring portion wise 10.6 g. bromocyan whereby the temperature is not allowed to rise above 40. After 1 hour the obtained compound is extracted with methylenchloride, washed with 20 ml. 2 N sodium hydroxide and twice with 100 ml. water. After drying and evaporating of the methylenchloride solution the residue is recrystallized from ethyl acetate and yields the l-[p (2 acetamido-ethyl)-phenylsulfonyl] 2 imino 3 n butyl-S-methyl-imidazolidine, M.P. 98-99".
Example 40 14.7 g. N-(Z-chlor-ethyl)-N-propyl-cyanamide and 27.0 g.
p-(2 butyramido-ethyl)-benzenesulfonamide the l-[p- (Z-butyramido-ethyl)-phenylsulfonyl) 2 imino 3 propyl-imidazolidine, M.P. 114-116;
14.7 g. N-(2 chlor-ethyl) N propyl-cyanamide and 33.4 g. p-[2 (3 methoxy-benzamido)-ethyl]-benzenesulfonamide the 1 [p [2 (3-methoxybenzamido)-- ethyl] phenylsulfonyl] 2 imino 3 propylimidazolidinc, M.P. 144-147;
14.7 g. N-(2 chloro-ethyl)-N-isopropyl-cyanamide and 25.6 g. p-(2 propionamido-ethyl)-benzenesulfonamide the l-[p (Z-propionamido-ethyl)-phenylsulfonyl] 2- imino-3-isopropylimidazoleidine, M.P. 11 1-1 12;
14.7 g. N-(2-chloro-ethyl) N isopropyl-cyanamide and 27.0 g. p-(Z-butyramido-ethyl)-benzenesulfonamide the 1-[p-(Z-butyr-amido-ethyl)-phenylsulfonyl] 2 imino- 3 isopropyl-imidazolidine, M.P. 139-140;
16.0 g. N-(2 chloro-ethyl) N butyl-cyanamide and 24.2 g. p-(Z-acetamido-ethyl)-benzenesulfonamide the l-[p (2 acetamido-ethyl)-phenylsulfonyl]-2-imino- S-butyl-imidazolidine, M.P. l30-131;
16.0 g. N (2-chloro-ethyl)-N-butyl-cyanamide and 28.4 g. p (2-methyl-butyramido-ethyl)-benzenesulfonamide the 1 [p-[2 (Z-methyl-butyramido)-ethyl]-phenylsulfonyl]-2-imino 3 butyl-imidazolidine, M.P. 114- 116;
16.0 g. N-(2 ch1oro-ethyl)-N-butyl-cyanamide and 28.4
g. p-(2 valeramido-ethyl)-benzenesulfonamide the 1- [p-(2-valeramido-ethyl) phenylsulfonyl] 2 imino-3- butyl-imidazolidine, M.P.
16.0 g. N-(Z-chloro-ethyl)-N-butyl-cyanamide and 33.9
g. p-[2 (2-chlorobenzamido)-ethyl]-benzenesulfonamide the 1-[p-[2 (2-chlorobenzamido)-ethyl)-phenylsulfonyl] 2 imino-3-butyl-imidazolidine, M.P. 157;
16.0 g. N-(2-chloro-ethyl)-N-butyl-cyanamide and 37.2 g.
p [1 (a,a,u-trifluorom-toluyl-amido)-ethyl]-benzenesulfonamide the 1-[p-(a,a,a-trifiuoro-m-toluyl-amido)- with water, dried and evaporated. The residue is crystallized from ethyl acetate and yields the pure l-[p-(Z-propionamido-ethyl)-phenylsulfonyl]-2-imino-3 n propylimidazolidine, M.P. 130-131.
In analogous way one obtains from:
40.2 g. N- [p- ('Z-butyramidoethyl)-phenylsulfonyl]-N-2- bromoethyl-cyanamide and 12.0 g. propylamine the 1- [p- (Z-butyramido-ethyl) -phenylsulfonyl] -2-imino- 3-propyl-imidazolidine-1 H O, M.P. 114-116";
46.6 g. N-[p-[2-( 3-methoxy-benzamido)-ethyl]-pheny1- sulfonyl]-N-2-bromoethyl-cyanamide and 12.0 g. propylamine the 1-[p-[2-(3-methoxy-benzamido)- ethyl] -phenylsulfonyl] -2-imino-3-propyl-imidazolidine, M.P. 144-147 38.8 g. N-[p-(Z-propionamido-ethyl)-phenylsulfonyl]- N-Z-brQmoethyI-cyan-amide and 12.0 g. isopropylamine the 1- [p-(2-propionamido-ethyl)-phenylsulfonyl] -2-imino-3-isopropylimidazolidine,
40.2 g. N-[p-(2-butyrarnido-ethyl)-phenylsulfonyl]-N- Z-bromoethyl-cyanamide and 12.0 g. isopropylamine the 1- [p- (Z-butyramido-ethyl -phenylsulfonyl) -2- imino-3-isopropyl-imidazolidine, M.P. 139-140";
37.4 g. N-[p-(Z-acetamido-ethyl)-phenylsulfonyl]-N- 2-bromoethyl-cyanamide and 14.6 g. butylamine the 1- [p- Z-acetamidoethyl -phenylsulfony1] -2-irnino-3- butyLimidazolidine, M.P. 130-13l;
38.8 g. N-[p-(Z-propionamido-ethyl)-phenylsulfonyl]- N-Z-bromoethyl-cyanamide and 14.6 g. butylamine the 1-[p-(Z-propionamidoethyl)-phenylsulfonyl]- 2-imino-3-butyl-imidazolidine, M.P. 137-138";
41.6 g. N-[p-[2-(2-methylbutyramido)-ethyl]-phenylsulfonyl]-N-2bromoethyl-cyanamide and 14.6 g. butylamine the 1-[p-[2- ('2-methyl-butyramido)- ethyl]-phenylsulfonyl]-2-imino-3-butylimidazolidine, M.P. 114-116";
41.6 g. N- [p-(2-valeramido-ethyl)-phenylsulfony1]- N-Z-bromoethyl-cyanamide and 14.6 g. butylamine the 1- [p-(2-valeramidoethyl)-phenylsulfonyl]-2-imino-3-butyl-imidazolidine, M.P. 130;
41.6 g. N-[p-(2-valeramido-ethyl)-phenylsulfonyl]-N-2- bromoethyl-cyanamide and 14.6 g. isobutyl-amine the l- [p- (2-valerarnido-ethyl) -phenylsulfonyl] -2- imino-3-isobutyl-imidazolidine, M.P. 130;
50.0 g. N- [p- [2- 2-methoxy-S-chloro-benzamido -ethyl] phenylsulfonyl]-N-2-bromoethyl-cyanamide and 14.6 g. isobutylamine the 1-[p-[2-(2-methoxy-5- chloro-benzamido)-ethyl]-phenylsulfonyl]-2-imino- 3-isobutyl-imidazolidine, M.P. 117-119 42.8 g. N-[p-(2-cyclohexane-carbox amido-ethyl)-phenylsulfonyl]-N-2-bromoethyl-eyanamide and 14.6 g. isobutylamine the 1-[p-(2-cyclohexane-carboxamidoethyl1-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine, M.P. 175-177";
37.4 g. N-[p-(2-acetamido ethyl)-phenylsulfonyl1-N-2- bromoethyl-cyanamide and 14.6 g. sec.butylamine the 1-[p-(Z-acetamido-ethyl)-phenylsulfonyl1-2- imino-3-sec.butyl-imidazolidine, M.P. 106-108";
38.8 g. N-[p-(Z-propionamido-ethyl)-phenylsulfonyl]- N-2-bromoethyl-cyauamide and 14.6 g. sec.butylamine the 1-[p-(2-propionamido-ethyl)-phenylsulfonyl]-2-imino-3-sec.butyl-imidazolidine, M.P.
40.2 g. N- [p-(Z-butyramido-ethyl)-phenylsu1fonyl]-N- Z-bromQethyI-cyanamide and 14.6 g. sec.butylamine the 1-[p-(Z-butyramido-ethyl)-phenylsulfonyl]- 2-imino-3-sec.butyl-imidazolidine, M.P.
40.2 g. N-[p-(Z-butyramido-ethyl)-phenylsulfonyl]-N- 2-bromoethyl-cyanamide and 14.6 g. tert.butylamine the 1-[p-(2-butyramido-ethyl)-phenylsulfonyl]-2-imino-3-tert.butyl-imidazolidine, M.P. 148-149";
41.6 g. N-[p-(2-isovaleramido-ethyl)-phenylsulfonyl]- N-Z-bromoethyl-cyanarnide and 14.6 g. tert.butylamine the 1-[p-(2-isovaleramido-ethyl)-phenylsul- 38 fonyl]-2-imino-3-tert.butylamidazolidine, M.P. 152-154" 41.6 g. N-[p-(Z-valeramido-ethylln-phenylsulfonyl]-N- Z-bromoethyl-cyanamide and 17 g. cyclopentylamine the 1-[D-(2-valeramido-ethy1)-phenylsulfonyl]-2-imino-3-cyclopentyl-irnidazolidine, M.P.
40.2 g. N- [p-(Z-butyramido-ethyl)-phenylsulfonyl]-N- 2-bromoethyl-cyanamide and 17 g. cyclopentylamine the 1-[p-(Z-butyramidoethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine, M.P.
44.2 g. N-[p-(2-cyclohexane'carboxamido-ethyD-phenyl]-N-Z-bromoethyl-cyanamide and 17 g. cyclopentylamine the 1-[p-(Z-cyclohexane-carboxamidoethyl) -phenylsulfonyl] -2-imino-3 -cyc1opentylimidazolidine, M.P. 178-179".
(b) The starting material is obtained on the following way:
To 10.6 g. cyanogen bromide in 40 ml. ether are dropped at --10" 4.3 g. ethylenimine in 20 ml. ether. To the formed in ether unsoluble Z-bromoethyl-cyanamide is added a suspension of 27.6 g. p-(2-propionamido-ethyl)-,
phenylsulfochloride in 100 ml. acetone. To the reaction mixture are dropped thereafter 52 ml. 2 N sodium hydroxide and it is stirred for 1 hour at room temperature.
Then the ether and acetone are removed in the rotary evaporator. The compound is extracted with methylenchloride. The solution is washed twice with 20 ml. water, dried and evaporated. The residue the N-[p-(Z-propionamido-ethyl)-pheny1sulfony1] N -2 bromethyl-cyanamide is a light yellow oil.
The used not isolated starting materials are obtained in analogous way\from 10.6 g. cyanogen bromide and 4.3 g. ethylenimine and:
Example 43 (a) 38.8 g. N [p-(Z-propionamido-ethyl)-phenylsulfonyl] N 2 bromoethyl-cyanamide in 200 ml. ethanol and 19.8 g. cyclohexylamine are refluxed for 1 hour.
Thereafter the reaction mixture is evaporated on the rotary evaporator. The residue is diluted with 50 ml. ethyl acetate and extracted two times with ml. 2 N hydrochloric acid. The aqueous phase is made alkaline with 2 N sodium hydroxide and extracted twice with ml. methylenchloride. The methylenchloride solution is washed with water, dried and evaporated. The residue crystallizes from ethyl acetate and yields the pure l-[p-(Z-propionamido-etl1y1) phenylsulfonyl] 2 imino-3-cyclohexylimidazolidine-hemihydrate, M.P. -112".
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3941804A (en) * 1973-07-27 1976-03-02 Ciba-Geigy Corporation 1-Heteroarylsulphonyl-2-imino-imidazolidines
US4591597A (en) * 1983-04-05 1986-05-27 Ciba-Geigy Corporation Antidiabetic iminosulphonamides
US5264426A (en) * 1991-09-30 1993-11-23 Bayer Aktiengesellschaft Phosphorylated diazacycloalkanes
EP1193256A1 (en) * 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Pharmaceutically active benzsulfonamide derivatives as inhibitors of JNK proteins
WO2003010164A1 (en) * 2001-07-23 2003-02-06 Applied Research Systems Ars Holding N.V. Arylsulfonamide derivatives as c-jun-n-terminal kinases (jnk's) inhibitors

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US3941804A (en) * 1973-07-27 1976-03-02 Ciba-Geigy Corporation 1-Heteroarylsulphonyl-2-imino-imidazolidines
US4591597A (en) * 1983-04-05 1986-05-27 Ciba-Geigy Corporation Antidiabetic iminosulphonamides
AU579997B2 (en) * 1983-04-05 1988-12-22 Ciba-Geigy Ag Iminosulphonamides and processes for the manufacture thereof, pharmaceutical preparations containing such compounds, and their use
US5264426A (en) * 1991-09-30 1993-11-23 Bayer Aktiengesellschaft Phosphorylated diazacycloalkanes
JP2004523475A (en) * 2000-09-27 2004-08-05 アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein Jun kinase
WO2002026711A1 (en) * 2000-09-27 2002-04-04 Applied Research Systems Ars Holding N.V. Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein junkinases
US20040053917A1 (en) * 2000-09-27 2004-03-18 Serge Halazy Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein junkinases
EP1193256A1 (en) * 2000-09-27 2002-04-03 Applied Research Systems ARS Holding N.V. Pharmaceutically active benzsulfonamide derivatives as inhibitors of JNK proteins
US7417058B2 (en) 2000-09-27 2008-08-26 Laboratoires Serono S.A. Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein junkinases
US20080255222A1 (en) * 2000-09-27 2008-10-16 Applied Research Systems Ars Holding N.V. Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein junkinases
US8008341B2 (en) 2000-09-27 2011-08-30 Merck Serono Sa Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein junkinases
JP4927303B2 (en) * 2000-09-27 2012-05-09 メルク セローノ ソシエテ アノニム Pharmaceutically active benzsulfonamide derivatives as inhibitors of protein Jun kinase
WO2003010164A1 (en) * 2001-07-23 2003-02-06 Applied Research Systems Ars Holding N.V. Arylsulfonamide derivatives as c-jun-n-terminal kinases (jnk's) inhibitors
US20040248886A1 (en) * 2001-07-23 2004-12-09 Aykanian Arthur A. Pharmaceutically active sulfonamide derivatives as c-jun-n-terminal kinases (jnk's) inhibitors
AU2002331253B2 (en) * 2001-07-23 2008-04-03 Laboratoires Serono Sa Arylsulfonamide derivatives as C-JUN-N-terminal kinases (JNK'S) inhibitors
US20100029719A1 (en) * 2001-07-23 2010-02-04 Laboratoires Serono S.A. Arylsulfonamide derivatives as c-jun-n-terminal kinases (jnk's) inhibitors
US7683078B2 (en) 2001-07-23 2010-03-23 Laboratoires Serono S.A. Arylsulfonamide derivatives as C-Jun-N-Terminal Kinases (JNK's) inhibitors

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