US3291829A - Alkyl guanidines - Google Patents

Alkyl guanidines Download PDF

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US3291829A
US3291829A US92755A US9275561A US3291829A US 3291829 A US3291829 A US 3291829A US 92755 A US92755 A US 92755A US 9275561 A US9275561 A US 9275561A US 3291829 A US3291829 A US 3291829A
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lower alkyl
acid
amino
methyl
compounds
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Mull Robert Paul
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BASF Corp
Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
    • C07C281/18—Compounds containing any of the groups, e.g. aminoguanidine the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention concerns guanidino derivatives. More particularly, it relates to N-R -N-R -aminolower alkyl-guanidines, in which R represents a cycloaliphatic radical containing from three to eight, more particularly from five to seven, ring carbon atoms, and R stands for hydrogen, an aliphatic radical, a cycloaliphatic radical, a carbocyclic aryl radical, a carbocyclic aryl-aliphatic radical, a heterocyclic aryl radical or a heterocyclic aryl-aliphatic radical, salts or quaternary ammonium compounds thereof, as well as process for manufacturing such compounds.
  • a cycloaliphatic radical R containing from three to eight ring carbon atoms stands more especially for cycloalkyl, containing from three to eight, especially from five to seven, ring carbon atoms, e.g. cyclopentyl, cyclohexyl or cycloheptyl, as well as cyclopropyl, cyclobutyl, cyclooctyl and the like. It may also represent cycloalkenyl containing from five to eight, especially six, ring carbon atoms, e.g. 2-cyclohexenyl, 3-cyclohexenyl and the like, as well as 2-cyclopentenyl, 3-cycloheptenyl and the like.
  • cycloaliphatic radicals are unsubstituted or may contain as substituents lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, or analogous groups, or functional substituents, such as halogeno, e.g. fluoro, chloro and the like, lower alkoxy, e.g. methoxy, ethoxy and the like.
  • the group R which may also represent hydrogen, may stand for an aliphatic group, such as lower alkyl, containing preferably from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and the like, as well as n-pentyl, neopentyl, n-hexyl, isohexyl, n-heptyl and the like, or any other aliphatic group, as well as a cycloaliphatic group, such as described hereinbefore, particularly cycloalkyl, containing from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentyl, cyclohexyl and the like.
  • an aliphatic group such as lower alkyl, containing preferably from one to four carbon atoms, e.g. methyl, ethyl, n-propy
  • the group R may also represent carbocyclic aryl, primarily monocyclic carbocyclic aryl, e.g. phenyl, or bicyclic carbocyclic aryl, e.g. l-naphthyl or Z-naphthyl.
  • Such radicals may be unsubstituted or may contain substituents; one or more than one of the same or different substituents may be attached to any of the available carbon atoms.
  • Substituents are, for example, lower alkyl, e.g.
  • N-methyl-amino, N-ethylamino and the like or particularly N,N-disubstituted amino, for example, N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, or
  • halogeno-lower alkyl e.g., trifluoromethyl and the like, or
  • R may also stand for a carbocyclic aryl-aliphatic atent radical, such as a monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like, and phenyl-lower alkyl, in which phenyl is substituted as shown hereinabove.
  • a carbocyclic aryl-aliphatic atent radical such as a monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like, and phenyl-lower alkyl, in which phenyl is substituted as shown hereinabove.
  • Heterocyclic aryl radicals R are primarily monocyclic or bicyclic heterocyclic aryl radicals, which contain one or more than one sulfur, oxygen and/ or nitrogen atom as ring members, and which are preferably pentacyclic or hexacyclic heterocyclic radicals.
  • Such radicals are represented, for example, by monocyclic mono-azacyclic aryl, for example, pyridyl, e.g. Z-pyridyl, 3-pyridyl, 4- pyridyl and the like, bicyclic mono-azacyclic aryl, for example, quinolyl, e.g.
  • 2-quinolyl, 4-quinolyl and the like monocyclic di-azacyclic aryl, for example, pyridazinyl, e.g. 3-pyridazinyl and the like, pyrimidyl, e.g. 2-pyrimidyl, 4-pyrimidyl and the like, pyrazinyl, e.g. Z-pyrazinyl, pyrryl, e.g. 2-pyrryl and the like, monocyclic thiacyclic aryl, for example, thienyl, e.g. 2-thienyl and the like, or monocyclic oxacyclic aryl, for example, furyl, e.g. 2- furyl and the like.
  • the above described heterocyclic radicals are unsubstituted or may contain as substituents one of those previously described as being attached to a carbocyclic aryl radical.
  • heterocyclic aryl-aliphatic radicals representing R such as monocyclic heterocyclic aryllower alkyl, in which the heterocyclic aryl radical has the previously given meaning;
  • pyridyl-lower alkyl e.g. 2- pyridlymethyl, 4-pyridylmethyl and the like, represent heterocyclic aryl-aliphatic radicals.
  • the lower alkyl portion, linking the N-R -N-R amino group with the guanidino group, is represented by lower alkylene containing from one to seven carbon atoms.
  • lower alkylene contains from two to three carbon atoms, which separate the N-R -N-R amino portion from the guanidino group by the same number of carbon atoms; such radicals are 1,2-ethylene, l-methyl-l,2-ethylene, 2-methyl-l,2-ethylene or 1,3-propylene.
  • Other lower alkylene radicals are, for example, methylene, 1,1-ethylene, 2,3-butylene, 1,3-butylene, 1,4- butylene, l,4 pentylene or 1,5-pentylene and the like.
  • the guanidino group may be represented by the formula:
  • each of the radicals R R and R stands primarily for hydrogen. They may also represent a hydrocarbon, particularly an aliphatic hydrocarbon, radical, such as lower alkyl, e.g. methyl, ethyl, n-p-ropyl, isopropyl and the like.
  • One of the radicals R and R may also be an acyl radical; an acyl radical may be, for example, the radical of a lower aliphatic carboxylic acid, for example, a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and the like, a substituted lower alkanoic acid, e.g.
  • benzoic 4- hydroxybenzoic, 4-methoxy-benzoic, 3,4-dimethoxybenzoic, 3,4,5-trimethoxy-benzoic, 4-O-ethoxycarbonyl-syringic, 3,4-dicl1lorobenzoic, 3-N,N-dimethylaminobenzoic, 4- nitrobenzoic acid and the like or a bicyclic carbocyclic aryl carboxylic acid, e.g. l-naphthoic, Z-naphthoic acid and the like, or a heterocyclic aryl carboxylic acid, for example, monocyclic heterocyclic aryl carboxylic acids, e.g. nicotinic, isonicotinic, 2-furoic acid and the like.
  • Salts of the new compounds of this invention are particularly therapeutically acceptable, non-toxic acid addition salts, such as those with inorganic acids, for example,
  • mineral acids e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or those with organic acids, such as organic carboxyl'ic acids, e.g. acetic, propionic, glycolic, lactic, pyruvi-c, oxalic, malonic, suocinic, maleic, fum-aric, malic, tartaric, citric, ascorbic, hydroxymaleic, di-
  • hydroxybenzoic anthranilic, cinnamic, mandelic, salicylic, 4-aminosalicylic, Z-phenoxybenzoic, Z-acetoxybenzoic and the like, or organic sulfonic acids, e.g. methane sulfonic, ethane snlfonic, Z-hydroxyethane sulfonic, p-toluene sulfonic acid and the like.
  • Semi-, monoor poly-salts may be formed.
  • the new guanidine compounds of this invention may also form quaternary ammonium compounds particularly quaternary ammonium salts with lower alkyl halides, e.g. methyl, ethyl, propyl or isopropyl chloride, bromide or iodide and the like, with di-lower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, with lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate and the like, or any other suitable reactive esters of alcohols with strong acids.
  • lower alkyl halides e.g. methyl, ethyl, propyl or isopropyl chloride, bromide or iodide and the like
  • di-lower alkyl sulfates e.g. dimethyl sulfate,
  • quaternary ammonium hydroxides and salts which may be formed from quaternary ammonium hydroxides by reacting the latter with inorganic acids other than hydrohalic or sulfuric acids, or with organic carboxylic acids, such as those used for the preparation of the acyl derivatives mentioned hereinabove.
  • the new guanidine derivatives of this invention reduce the norepinephrine content of peripheral sympathetic nerves or interfere with the release of norepinephrine from peripheral sympathetic nerves, and thus cause a reduction of the hypertensive effect resulting from sympathetic nerve stimulation.
  • the compounds of this invention are useful as antihypertensive agents to relieve hypertensive conditions, particularly those of neurogenic nature.
  • R represents cycloalkyl containing from three to eight, especially from five to seven, ring carbon atoms
  • R represents hydrogen or lower alkyl
  • A stands for alkylene containing from two to three carbon atoms and separating the guanidino from the amino group by from two to three carbon atoms, and therapeutically acceptable acid addition salts thereof, particularly those with mineral acids, e.g., hydrochloric, sulfuric, phosphoric acid and the like.
  • the compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contains the new guanidino-compounds or salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration.
  • a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration.
  • substances which do not react with the new compounds such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol polyalkylene glycols, petroleum jelly or any other known carrier for medicaments.
  • the pharmaceutical preparations may be in solid form, for example, as tablets, dra'gees, capsules and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers and the like. They also may contain, in combination, other therapeutically useful substances.
  • the new guanidine compounds of this invention may be prepared by converting in an N-R -N-R -lower alkylene-diamine, in which R and R have the previously given meaning, and in which the second amino group contains at least one hydrogen atom, or a salt thereof, the amino group, containing at least one hydrogen atom, into a guanidino group and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting compound into its acyl derivative, and/ or, if desired, converting a free compound into a salt or a quaternary ammonium compound thereof.
  • the reagents of choice for the conversion of an amino group into a guanidino group are S-lower alkyl-isothioureas of the formula:
  • the starting material in which the amino group containing at least one hydrogen atom, is above all an unsubstituted amino group, but may also represent a monosubstituted amino group, such as an N-lower alkyl-amino group, e.g. N-methylamino, N-ethylamino and the like, is generally used in the form of its free base.
  • the reaction is carried out by contacting the starting material with the reagent, preferably in the presence of a solvent, the choice of which depends primarily on the solubility of the reactants.
  • a solvent such as lower alkanols, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, ethers, e.g. diethyleneglycol dimethylether, p-dioxane, tetrahydrofuran and the like, ketones, e.g. acetone, ethyl methyl ketone and the like, lower alkanoic acids, e.g. acetic acid and the like, formamides, e.g. formamide, dimethylformarnide and the like, or aqueous mixtures of such solvents are preferred di-luents.
  • lower alkanols e.g. methanol, ethanol, propanol, isopropanol,
  • the reaction may be carried out at room temperature, or, if necessary, at an elevated temperature, for example, on the steam bath or at the boiling temperature of the solvent.
  • An absence of oxygen may be achieved by performing the reaction in the atmosphere of an inert gas, e.g. nitrogen, and, if necessary, it may be carried out under pressure in a closed vessel.
  • R R and R have the previously given meaning, or their salts with mineral acids.
  • isourea derivatives are used in the same way as the above-described, corresponding isothiourea reagents; O-methyl-isourea sulfate represents a preferred reagent.
  • the S-lower alkyl-isothioureas or O-lower alkyl-isoureas may be obtained by alkylating thioureas or ureas, with a lower alkyl halide, e.g. methyl or ethyl chloride, bromide or iodide and the like, or with a dilower alkyl-sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like.
  • a lower alkyl halide e.g. methyl or ethyl chloride, bromide or iodide and the like
  • dilower alkyl-sulfate e.g. dimethyl sulfate, diethyl sulfate and the like.
  • cyanamides having the formula:
  • the reaction may be carried out, for example, by heating a mixture of the cyanamide compound wit-h the N-R -N-R -amino-lower alkylene-diamine, preferably in the form of a salt, particularly of a mineral acid addition salt, thereof, such as the hydrochloride, hydrobr-omide, sulfate and the like.
  • a resulting melt may then be dissolved in a solvent, such as a lower alkanoic acid, e.g. acetic acid, and the like, and the desired product may be isolated, for example, by crystallization and the like.
  • the reaction may also be performed in the presence of a suitable solvent, such as a lower alkanol, e.g. ethanol and the like.
  • a suitable solvent such as a lower alkanol, e.g. ethanol and the like.
  • the salt used as the starting material may also be formed at the site of the reaction by performing the latter in the presence of an acid, particularly of a concentrated aqueous mineral acid, e.g. hydrochloric acid and the like.
  • the cyanamide reagent may also be formed in situ; for example, l-nitroso-3-methyl-guanidine furnishes the N-methyl-cyanamide during the reaction, and the latter then reacts with the amine to form the desired guanidino compound.
  • the reaction may proceed exothermically, and, if necessary, may be maintained by heating, for example, to from about 80 to about 200; the atmosphere of an inert gas, e.g. nitrogen, may be advantageous.
  • a third modification of the general procedure for the manufacture of the compounds of this invention comprises reacting an R -N-R -amino-lower alkylene-diamine, in which R and R have the previously given meaning, and in which the second amino group contains at least one hydrogen atom with a salt of a l-guanyl-pyrazole.
  • a salt of a l-guanyl-pyrazole is primarily a salt with a mineral acid, such as, for example, nitric acid; the pyrazole nucleus of such reagent may contain additional substituents, particularly lower alkyl, e.g. methyl, ethyl and the like.
  • 1-guanyl-3,S-dimethyl-pyrazole salts represent the preferred reagents.
  • the reaction may be carried out in the absence of a solvent, for example, by fusing the two reactants, or in the presence of a diluent, such as, for example, a lower alkanol, e.g. ethanol and the like; advantageously, contact with carbon dioxide should be avoided, for example, by performing the reaction in the atmosphere of an inert gas, e.-g. nitrogen.
  • the reaction mixture is preferably heated, for example, to the melting point of the mixture or to the boiling point of the solvent.
  • N-R -N-R -lower alkyl-diamines in which R and R have the previously given meaning, and in which the second amino group contains at least one hydrogen atom and the salts thereof, used as the starting materials, are known, or, if new, may be prepared according to known methods.
  • They may be prepared by reacting an N-R -N-R -amine with a halogeno-lower alkyl-nitrile, in which halogeno represents, for example, chloro, bromo and the like, or with a lower alkene-nitrile, in which the double bond is activated by the nitrile group in such fashion, that it adds to the secondary amino group, and converting in a resulting N-R -N-R -amino-lower alkyl-nitrile, the nitrile group to a methylene-amino group by reduction.
  • halogeno represents, for example, chloro, bromo and the like
  • the latter may be carried out, for example, by catalytic hydrogenation, such as, treatment with hydrogen in the presence of a catalyst containing a metal of the eighth group of the Periodic System, e.g. palladium on charcoal or Raney nickel, or, preferably, by treatment with a light metal hydride, for example, an aluminum hydride, such as lithium aluminum hydride, sodium aluminum hydride, magnesium aluminum hydride, aluminum borohydride, aluminum hydride and the like, which hydrides may be used, if desired, in the presence of an activator, such as aluminum chloride.
  • catalytic hydrogenation such as, treatment with hydrogen in the presence of a catalyst containing a metal of the eighth group of the Periodic System, e.g. palladium on charcoal or Raney nickel
  • a light metal hydride for example, an aluminum hydride, such as lithium aluminum hydride, sodium aluminum hydride, magnesium aluminum hydride, aluminum borohydride, aluminum hydride and the like, which hydrides may be used,
  • the compounds of the present invention may also be prepared by converting in an N-R -N-R -N'-R -lower alkylene-diamines, in which R and R have the previously given meaning, and R represents a substituent capable of being converted into an amidino group, or a salt thereof, the substituent R into an amidino group, and, if desired, carrying out the optional steps.
  • the substituent R may contain a carbon atom, which is attached to the nitrogen atom of the amino ignoup in the starting material; to this canbon atom may be connected a nitrogen atom.
  • Said carbon atom may carry an additional nitrogen atom, as well as other hetero atoms, such as, for example, oxygen or sulfur.
  • the greater part of these starting materials may be converted to the desired tguanidino derivatives by ammonolysis or amin olysis.
  • a cyanamide may be converted into a guanidino derivative by treatment with ammonia or an ammonia-furnishing reagent, as well as with an amine, such as an N-lower alkyl-amine.
  • This reaction may be carried out, for example, by treating the cyanamide compound with liquid ammonia under pressure and at an elevated temperature, if desired, in the presence of an anion capable of forming a stable salt with a resulting guanidine; ammonium acetate, ammonium sulfate, ammonium chloride and the like maybe used as anion sources.
  • Ammonia may be replaced by ammonia furnishing ammonium salts; such salts are, for example, ammonium monohydro-gen phosphate, which may be used under pressure and at an elevated temperature, or ammonium nitrate, whereby a salt, such as, for example, an alkaline earth metal, e.g. calcium and the like, salt or an alkali metal, e.g. sodium, potassium and the like, salt of the cyanamide starting material is preferably used, which may be reacted with the ammonium nitrate in the presence of catalytic amounts of water.
  • a salt such as, for example, an alkaline earth metal, e.g. calcium and the like, salt or an alkali metal, e.g. sodium, potassium and the like, salt of the cyanamide starting material is preferably used, which may be reacted with the ammonium nitrate in the presence of catalytic amounts of water.
  • R2 lh-fi-lower alkyl-N-C EN in which R R and R have the previously given meaning, and salts thereof, may be prepared, for example, by treating an N-R -N-R -lower alkylene-diamine, in which the second amino group contains a hydrogen atom, with a cyanogen halide, e.g. cyanogen chloride, cyanogen bromide and the like, advantageously in equivalent amounts and preferably in an inert solvent, such as, for example, diethylether and the like.
  • a cyanogen halide e.g. cyanogen chloride, cyanogen bromide and the like
  • a carbarnyl substituent R in an N-R -N-R -N'-R lower alkylene-diamine may be converted into the desired amidino group by treatment with ammonia, preferably, in the presence of a dehydrating agent, such as, for example, phosphorous pentoxide and the like.
  • a dehydrating agent such as, for example, phosphorous pentoxide and the like.
  • This reaction may be carried out at an elevated temperature in a closed vessel; temperature and pressure may be reduced in the presence of a non-aqueous solvent and/ or of a reaction accelerator, such as finely disperse-d nickel, aluminum, aluminum oxide and the like.
  • Ammonia may he replaced by an amine, such as an N-lo was alkyl-arnine, to form in the final product a substituted guanidino group.
  • a thiocarbamyl group R which together with the amino group in an N-R -N-R -N-R -lower alkylene-diamine forms a thiourea group, may be converted into an amidino group by treatment with ammonia, for example, in the presence of water, and/or of a nonhydrolytic solvent, such as, for example, toluene and the like, and in the presence of a desulfurizing agent.
  • the latter is selected advantageously from basic oxides, basic carbonates and the like, of heavy metals, such as lead, zinc, cadmium, tin, mercury and the like; desulfurizing compounds are, for example, lead oxide, mercuric oxide, lead hydrogen carbonate and the like.
  • Mercuric chloride may also he used. This ammono'lysis procedure, is preferably carried out at an elevated temperature, and, if necessary, in a closed vessel, primarily to avoid loss of ammonia.
  • An amine such as an N-lower alkyl-amine, may replace ammonia, and N-substituted guanidino derivatives may be formed.
  • a solvent for example, water, if desired, containing a small amount of an acid, such as a mineral acid, e. g.
  • urea or thiourea compounds used as starting materials, may also be obtained by ammonolysis or aminolysis of reactive functional derivatives of N-(N-R -N-R -amino-loweralkyD-carbamic acids, as well as N-(N-R -N-R -amino-lower aIkyD-thiocarbamic acid having the general formula:
  • Such reactive functional derivatives are primarily esters, for example, lower alkyl, er". methyl, ethyl and the like, esters or halides, eug. chlorides and the like.
  • these carbamic and thiocarbamic acids yield the desired urea or thiourea derivatives, respectively.
  • Ammonia may also 'be replaced by an amine, such as an N lower alkylarnine.
  • Ammonolysis may be carried out by treatment with ammonia, either in its liquid form or as a solution, such .as an aqueous solution, thereof, whereby an elevated temperature and/or a closed vessel, as well as the presence of an ammonium salt, such as ammonium chloride and the like, may be required.
  • dehydrating agents or desulfurizing agents such as those previously described, may be present in the reaction medium, depending on the type of starting material used.
  • An amine such as an N-lower alkyl-amine, may also be used for the conversion of the isoureas and isothioureas into guanidino derivatives containing substituted guanidino groups.
  • the isourea and isothiourea compounds used as the starting material in the above reaction may be obtained, for example, from the previously mentioned urea and thiourea derivatives by treatment of the latter, or of a metal salt thereof, sueh as an alkali metal, e.g. sodium, potassium and the like, salt thereof, with a lower alkyl halide, e.g. methyl or ethyl chloride, bromide or iodide and the like, or with a di-lower alkyl sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like.
  • a metal salt thereof sueh as an alkali metal, e.g. sodium, potassium and the like, salt thereof
  • a lower alkyl halide e.g. methyl or ethyl chloride, bromide or iodide and the like
  • a di-lower alkyl sulfate e
  • Such reaction may be carried out in the presence of a solvent, the selection of which depends on the type of reagents used; a free urea or thiourea compound may be used in the presence of water or a lower alkanol, e.g. methanol, ethanol and the like, whereas an alkali metal salt of a u-rea or thiourea compound may be reacted in the presence of a hydrocarbon, e.-g. toluene and the like, solution.
  • a solvent the selection of which depends on the type of reagents used
  • a free urea or thiourea compound may be used in the presence of water or a lower alkanol, e.g. methanol, ethanol and the like
  • an alkali metal salt of a u-rea or thiourea compound may be reacted in the presence of a hydrocarbon, e.-g. toluene and the like, solution.
  • a cyanamidino substituent R which forms a cyanoguanidino group with the amino group of an N-R -N-R lower alkylene-diamine, in which the second amino group contains at least one hydrogen atom, may be converted into an amidino group by ammonolysis or aminolysis.
  • This reaction may be carried out by treatment with ammonia, as well as with an ammonium salt, e.g. ammonium chloride, ammonium nitrate, ammonium sulfate and the like, whereby these salts may also promote ammonolysis with ammonia itself.
  • Aminolysis of the starting materials may be carried out by treatment with an amine, such as an N-lower alkyl-amine, and N-substituted guani dine derivatives may be obtained.
  • a biguanido group may be formed inter-mediarily, which, upon further treatment with the ammonolysis reagent, may be converted to the desired guanidino group.
  • Such biguanido derivatives may be accessible through different procedures (as will be shown hereinbelow) and are, therefore, also useful as starting material for the formation of the desired guanidino compounds by treatment with one of the ammonolysis or aminolysis reagents described herein-before.
  • a cyano-guanidino derivative may also be converted into the desired guanidino compound by reductive cleavage of the cyano group. Such cleavage may be carried out, for example, by electrolytic reduction on a cathode, such as, for example, a lead cathode.
  • R R R and R have the previously given meaning, and their salts, which compounds may be converted to the desired guanidino groups by the abovedescribed ammonolysis, aminolysis or reduction, may be prepared by treatment of S-lower alkyl-cyano-isothioureas of the formula:
  • R R R and R have the previously given meaning, with ammonia, for example, in the presence of a lower alkanol, e.g. ethanol and the like, preferably in a sealed tube, or with an amine, such as an N-lower alkyl-amine.
  • a lower alkanol e.g. ethanol and the like
  • an amine such as an N-lower alkyl-amine.
  • cyanoaguanidine derivatives are obtained by ammonolysis or aminolysis from S-lower alkyl-cyanisothiourea compounds having the above-given formula
  • the latter compounds may, therefore, directly serve as starting materials for the preparation of the guanidino compounds of this invention.
  • Ammonolysis or ammolysis of the cyanoisothiourea compounds to the latter may be carried out by treatment with ammonia or an amine in the presence of an anion of a strong acid, such as a halide, a nitrate, a sulfate ion and the like, for example, by the respective ammonium salts.
  • the S-lower alkyl-cyanoisothioureas of the above formula or their salts may be obtained, for example, by treating an N-R -N-R -amino-lower alkyl-isothiocyanate with an alkali metal, e.g. sodium, cyanamide and alkylating a resulting 1-[(N-R -N-R -amino)lower alkyl]-3-cyano-2-thiourea, preferably a salt thereof, with a lower alkyl halide, e.g. methyl or ethyl chloride, bromide or iodide and the like, or with a di-lower alkyl sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like, as previously described in the preparation of the S-lower alkyl-isothioureas used as starting material for the preparation of the desired guanidines.
  • R R R and R have the previously given meaning, and salts thereof.
  • These compounds may also be prepared, for example, by reacting an N-R -N-R amino-lower alkyl-amine, in which the second amino group carries at least one hydrogen atom, with dicy-anodiamide, preferably in the presence of a complex metalforming salt, e.g. copper sulfate and the like.
  • a resulting biguanido complex metal salt, such as the copper complex salt thereof may be liberated to form the free compounds by treatment with an acid, such as a mineral acid, e.g. sulfuric acid and the like, to form the free compound.
  • an acid such as a mineral acid, e.g. sulfuric acid and the like
  • ammonolysis with ammonia or ammonia-furnishing reagents may be replaced by aminolysis with amines, particularly N-lower alkylamines, e.g. N-rnethylamine, N-ethylamine and the like.
  • aminolysis reactions provide for the formation of substituted guanidino groups mentioned bereinabove.
  • the guanidino compounds may also be obtained by hydrolysis of an N-R -N-R -N'-R -lower alkylene-diamine, in which R and R have the previously given meaning, and R represents a substituent capable of being hydrolyzed to an amidino group.
  • R represents a substituent capable of being hydrolyzed to an amidino group.
  • RiN-lower alkyl-N-C in which R R R and R have the above-given meaning, and X represents oxygen or sulfur, and salts thereof, which may be converted to the desired guanidino compounds by hydrolysis, may be obtained, for example, by reacting an N-k -N-R -amino-lower alkylcyanamide with ametal cyanate or thiocyanate, particularly an alkali metal, e.g. sodium or potassium, cyanate or thiocyanate in a neutral medium, for example, in the presence of water.
  • an alkali metal e.g. sodium or potassium
  • N-R -N-R -N'-R -l0 alkylene-diamines, in which a carbon atom with a substituting nitrogen atom of the group R is attached to the second amino group
  • other N-R -N-R -N-R -lower alkylene-diamines in which the R represents a substituent convertible into an amidino group, may be useful in the conversion into the desired N-R -N-R -amino-lower alkyl-guanidines.
  • a conversion intermediates may be formed, which may have the previously given characteristics, i.e. the carbon atom of the group R carries a nitrogen atom.
  • Such groups are, for example, ester groups, formed by a car-boxyl, a thionocarboxyl, a thiol'ocarboxyl or a dithiocarboxyl group with a lower alkanol, as well as halogeno-carbonyl or halogeno-thionocarbonyl groups, in which halogen-o represents primarily chloro.
  • Particularly useful starting materials are, for example, the reactive functional derivatives of carbamic acids and thiocarbamic acids, having the formulae:
  • esters for example, lower alkyl, e.g. methyl, ethyl and the like, esters, or halides, e.g. chlorides, of such acids yield upon iammouolysis the corresponding urea and thioure-a derivatives.
  • an N-(N-R -N-R amino-lower alkyD-carbamic acid ester may be converted directly tot he desired guanidino compound.
  • an ester of an N-(N-R -N-R -aminolower alkyl)-thiocarbamic acid may be subjected to ammonolysis to yield directly the desired guanidino compound, for example, in the presence of a desulfurizing reagent, such as one of those previously shown in the conversion of a thiourea derivative int-o the desired guanidino compounds, e.g. lead oxide and the like.
  • the carbarnic and thiocarbamic acid derivatives used as the starting materials may be prepared according to procedures used for the manufacture of known analogs. For example, upon treatment of an N-R -N-R -lower alkylene-diamine, in which the second amino group contains at least one hydrogen atom with phosgene or thiophosgene, which reagents may be used in a slight excess over the amines, the (N-R -N-R -amino)-lower alkylisocyanates and (N-R -N-R -amino)-lo-wer alkyl-isothiocyanates, respectively, may be formed.
  • Such cyanate and isothiocyanate compounds may then be converted into esters of carbamic or thi-ocarbamic acids by treatment with an alcohol, for example, a lower alkanol, e.g. methanol, ethanol and the like, or into the corresponding thiolesters, by treatment with a mercaptan, such as a lower alkyl-mercaptan, e.g., methylmercaptan, ethylmercaptan and the like.
  • an alcohol for example, a lower alkanol, e.g. methanol, ethanol and the like
  • a mercaptan such as a lower alkyl-mercaptan, e.g., methylmercaptan, ethylmercaptan and the like.
  • the above derivatives may also be obtained by reacting an N-R -N-R -lower alkylenediamine, in which the second amino group contains at least one hydrogen atom, with a carbonic acid lower alkyl ester, or, particularly a dithiocarbonic acid lower alkyl ester, as well as with a lower alkyl ester of a halogeno-formic acid, such as chloroformic acid, or, primarily, of a halogeno-thioformic acid, such as chlorothioforrnic acid.
  • a salt of an N-R -N-R -l-ower :alkylene-diamine, in which the second amino group contains at least one hydrogen atom, particularly a hydrohalide, e.g. hydrochloride, thereof, when reacted with phosgene or thiophosgene at an elevated temperature, preferably in a closed vessel, yields the desired N-(N-R -N-R -arninolower alkyl)-carbamic acid chloride and N-(NR -NR amino-lower alkyl)-thio carbamic acid chloride, respectively.
  • a hydrohalide e.g. hydrochloride
  • An additional general procedure for the preparation of the compounds of this invention comprises converting in an N R N R amino lower alkane carboxylic acid guanide or a guanidino-lower alkane carboxylic acid N-R -N-R -amide, the carbonyl group of the amide portion to a methylene group, and, if desired, carrying out the optional steps.
  • the reduction of the carbonyl portion of the amide groups may be carried out according to known methods, for example, by treatment with an aluminum hydride, particularly an alkali metal aluminum hydride, e.g. lithium aluminum hydride, sodium aluminum hydride and the like, or an alkaline earth metal aluminum hydride, e.g.
  • an aluminum hydride particularly an alkali metal aluminum hydride, e.g. lithium aluminum hydride, sodium aluminum hydride and the like, or an alkaline earth metal aluminum hydride, e.g.
  • an inert solvent particularly an ether, such as a di-lower alkyl ether, e.g. diethyl ether, di-isopropyl ether and the like, a carbocyclic aryl lower ether, e.g. anisole and the like, a cyclic ether, e.g. tetrahydrofuran, p-dioxane and the like, or any other suitable solvent, and, if desired, at an elevated temperature and/or in the atmosphere of an inert gas, e.g. nitrogen.
  • an inert gas e.g. nitrogen.
  • Replacement of the oxygen atom of a carbonyl group by two hydrogen atoms in an amide compound may also be accomplished by treatment with hydrogen in the presence of certain catalysts, such as, for example, a copperchromium catalyst and the like; hydrogenation may be carried out in the presence of an inert solvent and, if necessary, under increased pressure, as Well as by electrolytically reducing the amido derivatives according to known methods, for example, on a cathode of a high overpotential such as, for example, mercury, lead amalgam, lead cathode and the like.
  • catalysts such as, for example, a copperchromium catalyst and the like
  • hydrogenation may be carried out in the presence of an inert solvent and, if necessary, under increased pressure, as Well as by electrolytically reducing the amido derivatives according to known methods, for example, on a cathode of a high overpotential such as, for example, mercury, lead amalgam, lead cathode and the like.
  • the starting materials used in the above reduction procedure may be prepared, for example, by treating a reactive functional derivative of an N-R -N-R -amino-lower alkane carboxylic acid with a guanidine, or a reactive functional derivative of a guanidino-lower alkane carboxylic acid with an N-R -N-R amine to form the desired amide compounds.
  • Reactive functional derivatives of carboxylic acids are, for example, esters, such as lower alkyl, e.g. methyl, ethyl and the like, esters, or activated esters, which are particularly useful for the formation of amide bonds, such as esters with reactive mercaptan compounds, e.g.
  • esters may be prepared according to methods which are used for the manufacture of analogous esters.
  • Other reactive functional derivatives of acids are the acid addition salts of acid halides, particularly the hydrochloride of an acid chloride, which may be prepared according to standard methods.
  • the treatment of these reactive functional derivatives of carboxylic acids with the amino compounds may be carried out, for example, by reacting a salt of acid halide, particularly the hydrochloride of an acid chloride with the amine, preferably in a polar, but non-hydroxylat'ed solvent, such as, for example, N,N-dimethylforrnamide,
  • a modification of the above procedure comprises converting in an N-R -N-R -amino-lower alkane thiocarboxylic acid guanide or a guanidino-lower alkane thiocarboxylic acid N-R -N-R -amide, the thiocarbonyl group of the thioamide portion into a methylene group, and, if desired, carrying out the optional steps.
  • Replacement of the sulfur in the above-mentioned thioamides by two hydrogens may be achieved by desulfurization, for example, with a freshly prepared hydrogenation catalyst, such as Raney nickel, in an alcohol solvent, e.g. methanol, ethanol and the like, if desired, in the presence of hydrogen, or electrolytic reduction as outlined hereinabove for the reduction of the amides.
  • a freshly prepared hydrogenation catalyst such as Raney nickel
  • the thioamides used as the starting materials in this modification may be prepared from the corresponding, previously described amides, for example, by treatment with phosphorus trisulfide, phosphorus pentasulfide and the like.
  • a modification may consist in electrolytically reducing the amide in the presence of an alkali metal sulfide, e.g. sodium sulfide and the like, thereby forming the thioamide as a non-isolated intermediate.
  • Compounds of the present invention may also be pre pared by treating an N-R -N-R -amine, in which R and R have the above-given meaning, or a salt thereof, with a reactive ester of a guanidino lower alkanol, in which the 1.3 lower alkanol portion contains at least two carbon atoms, which separate the hydroxyl from the guanidino group by at least two carbon atoms, or a salt thereof, and, if desired, carrying out the optional steps.
  • a reactive ester of a guanidino-lower alkanol is particularly an ester with a strong inorganic acid, such as a mineral acid, particularly a hydrohalic acid, e.g. hydrochloric, hydrobromic, hydriodic acid and the like, or with a strong organic acid, particularly a strong organic sulfonic acid, such as monocyclic carbocyclic aryl sulfonic acid, e.g. p-toluene sulfonic acid and the like.
  • Such esters are, therefore, primarily guanidino-lower alkyl halides, e.g. chlorides, bromides and the like, or especially salts with hydrohalic acids, e.g. hydrochloric, hydrobromic acid and the like, thereof.
  • the salts may be lib erated at the site of the reaction by treating the salt with the necessary amount of an alkaline reagent.
  • This reaction may be carried out, for example, by adding a basic reagent, such as, for example, an alkali metal, e.g. sodium or potassium, in liquid ammonia, or an alkali metal, e.g. sodium or potassium, carbonate. It is preferably performed in the presence of a solvent, the selection of which depends on the properties of the reagents; a lower alkanol, e.g. methanol, ethanol and the like, may be used with the salt of an ester of the guanidino-lower alkanol, whereas the free base may be reacted in the presence of a non-hydroxylic solvent, such as, for example, an ether, e.g.
  • a non-hydroxylic solvent such as, for example, an ether, e.g.
  • a hydrocarbon such as a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene, toluene and the like. It may be performed under cooling, or more preferably, at an elevated temperature, if desired, in a closed vessel under pressure, or in the atmosphere of an inert gas.
  • the reactive esters of guanidino-lower alkanols in which the lower alkanol portion contains at least two carbon atoms and separates the guanidino group from the hydroxyl group by at least two carbon atoms, and in which the nitrogen atoms of the guanidino group may be substituted as previously shown, and the salts thereof, which reagents are used as the starting materials in the above reaction, may be prepared by esterifying guanidino-lower alkanols.
  • a guanidinolower alkanol may be converted into a guanidino-lower alkyl halide by treatment with a thionyl halide, particularly thionyl chloride; such reaction may be carried out in the presence of an inert solvent, for example, a hydrocarbon, such as a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene, toluene and the like, or in any other suitable solvent.
  • a hydrocarbon such as a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene, toluene and the like, or in any other suitable solvent.
  • This procedure yields preferably the acid addition salt with a hydrohalic, e.g. hydrochloric, acid.
  • a guanidino-lower alkyl sulfonate particularly a p-toluene-sulfonate, may be prepared, for example, by treatment of the guanidino-lower alkanol with a sulfonyl halide, such as p-toluene-sulfonyl chloride, in the presence of a solvent, such as pyridine and the like.
  • a sulfonyl halide such as p-toluene-sulfonyl chloride
  • a modification of the above procedure comprises treating a reactive ester of an N-R N-R -amino-lower alkanol, in which R and R have the previously given meaning, or a salt thereof with a guanidine, and, if desired, carrying out the optional steps.
  • a reactive ester of an N-R -N-R -amino-lower alkanol is an ester with a strong inorganic or organic acid; N-R N-R -amino-lower alkyl halides, e.g. chlorides and the like, or N-R -N-R -amino-lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. p-toluene sulfonates and the like, or salts thereof are the preferred reagents.
  • the guanidines such as guanidine itself, as well as guanidines containing additional substituents which do not interfere with the reaction, may also be used in the form of their salts. The reaction is performed along the general procedure outlined hereinbefore.
  • the starting materials i.e. reactive esters of N-R -N- R -amino-lower alkanols are known and may be pre-.
  • guanidines may be acylated; this reaction may be carried out, for example, by treating the guanidine compound with the reactive derivative of a carboxylic acid, for example, with the halide, e.g. chloride and the like, or the anhydride of a carboxylic acid.
  • the acylation may be performed in the presence of an inert solvent, for example, a hydrocarbon, such as a lower alkane, e.g. hexane and the like, a monocyclic carbocyclic aryl hydrocarbon, e.g.
  • a tertiary organic base such as a liquid pyridine compound, e.g. pyridine, collidine and the like, or any other suitable diluent.
  • Acylation may also be achieved in the absence of a solvent, for example, by heating the guanidine compound or a salt thereof with the acylating reagent, for example, acetic acid anhydride and the like, in a sealed tube.
  • the new guanidine compounds may be obtained in the form of the free compounds or as the salts thereof.
  • a salt may be converted into the free compound in the customary way, for example, by treatment with a strong alkaline reagent, such as aqueous alkali metal hydroxide, e.g. lithium, sodium, potassium hydroxide and the like, a strong quaternary ammonium anion (hydroxyl ion) exchange resin and the like.
  • a free base may be transformed into its therapeutically useful acid addition salts by reacting the latter with an appropriate inorganic or organic acid, such as one of the above-mentioned acids. The reaction may be carried out, for example, in a solvent, such as, for example, a lower alkanol, e.g.
  • methanol, ethanol, propanol, isopropanol and the like an ether, e.g. diethylether, p-dioxane and the like, a lower alkyl lower alkanoate, e.g. ethyl acetate and the like, a halogenated hydrocarbon, e.g. methylene chloride and the like, or a mixture of such solvents, and isolating the desired salt.
  • Monoor poly-salts may be formed, as well as mixed salts; for example, a resulting half-sulfate salt, when treated with hydrogen chloride, yields the hy drochloride half-sulfate salt.
  • the new guanidine compounds of this invention may also form quaternary ammonium compounds, particularly those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, with di-lower alkyl-sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, or with lower alkyl lower'alkane sulfonates, e.g.
  • lower alkyl halides e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like
  • di-lower alkyl-sulfates e.g. dimethyl sulfate, diethyl sulfate and the like
  • lower alkyl lower'alkane sulfonates e.g.
  • the quaternary ammonium compounds may be obtained by reacting a resulting free base with a lower alkyl halide, e.g. methyl, ethyl, n-propyl, isopropyl chloride, bromide or iodide and the like, with a di-lower alkyl-sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like, or with a lower alkyl lower alkane sulfonate, e.g. methyl or ethyl methane or ethane sulfonate and the like.
  • a lower alkyl halide e.g. methyl, ethyl, n-propyl, isopropyl chloride, bromide or iodide and the like
  • a di-lower alkyl-sulfate e.g. dimethyl sulfate, diethyl sul
  • the quaternizing reaction may be performed in the absence or in the presence of a solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, a lower alkanone, e.g. acetone, ethyl methyl ketone and the like, an organic acid amide, e.g. formamide, N,N-dimethylformamide and the like, or a halogenated hydrocarbon, e.g. methylene chloride and the like.
  • a solvent such as, for example, a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, a lower alkanone, e.g. acetone, ethyl methyl ketone and the like, an organic acid amide, e.g. formamide, N
  • Resulting quaternary ammonium compounds may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting resulting quaternary ammonium halides with silver oxide, by treating quaternary ammonium sulfates with barium hydroxide, or quaternary ammonium salts with an anion exchanger, or by electrodialysis. From a resulting quaternary ammonium hydroxide there may be formed therapeutically suitable quaternary ammonium salts by treating the quaternary ammonium hydroxide with acids, for example, with those outlined hereinbefore as being useful for the preparation of acid addition salts.
  • the invention also comprises any modification of the general process, wherein a compound obtainable as an intermediate at any stage of the process is used as the starting material and the remaining step(s) of the process is (are) carried out; also included within the scope of the invention are any new intermediates.
  • Example I A solution of 10.0 g. of N-cyclohexyl-ethylenediamine and 9.8 g. of S-methyl-isothiourea sulfate in ml. of water is refluxed for four hours and is then concentrated under reduced pressure. The solid residue is recrystallized fom a mixture of n-butanol and Water (or ethanol and water) to yield the desired 2-(N-cyclohexylamin0)- ethyl-guanidine sulfate of the formula:
  • the Z-(N-cyclopentylamino)-ethyl-guanidine sulfate is prepared according to the above procedure by reacting N-cyclopentyl-ethyenediamine with S-methyl-isothiourea sulfate in water.
  • Example 2 A mixture of 5.0 g. of N-cyclohexyl-1,3-propy1enediamine and 4.5 g. of S-methyl-isothiourea sulfate in 30 ml. of water is refluxed for six hours and is then evapo' rated to dryness under reduced pressure.
  • the above sulfate salt is suspended in water, an excess of sodium hydroxide is added While cooling and the free base is extracted immediately with chloroform. The chloroform solution is dried, filtered and evaporated. The free base is converted into the dihydrochloride by treating a concentrated solution of the free base in ethanol with a solution of hydrogen chloride in ethanol and diluting the reaction mixture with diethylether, whereupon the salt precipitates.
  • R is cycloalkyl having 3 to 6 ring carbon atoms
  • R stands for a member selected from the group consisting of hydrogen and lower alkyl
  • A is lower alkylene having from two to three carbon atoms and separating the guanidino from the amino group by from two to three carbon atoms, and an addition salt thereof with a therapeutically acceptable acid.

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Cited By (13)

* Cited by examiner, † Cited by third party
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US3409669A (en) * 1963-12-13 1968-11-05 Evans Medical Ltd 2-(cyclohexylamino)-2-methyl-propylguanidine-1 and the salts and hydrate thereof
US3412105A (en) * 1966-01-05 1968-11-19 American Home Prod beta-aryl-n-guanidino-beta-alanines
US3454640A (en) * 1966-07-25 1969-07-08 Abbott Lab Alkoxy- or alkylthio-alkyleneaminoalkylguanidines
US3546227A (en) * 1966-12-01 1970-12-08 Sandoz Ag 2,3-dihydro-1h-benz(d,e)isoquinoline carboxamidines
US4271190A (en) * 1978-03-02 1981-06-02 Th. Goldschmidt Ag Guanidinium salts, processes for their manufacture as well as microbicidal preparations containing these compounds
EP0062844A1 (de) * 1981-04-09 1982-10-20 Beiersdorf Aktiengesellschaft Substituierte Benzo(de)isochinoline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US5612332A (en) * 1984-03-19 1997-03-18 Alteon Inc. Di- and triaminoguanidines, and methods of use
US5850840A (en) * 1995-11-15 1998-12-22 Alteon Inc. Methods for measurement and treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts
US5852009A (en) * 1984-03-19 1998-12-22 The Rockefeller University Compositions, including pharmaceutical compositions, for inhibiting the advanced glycosylation of proteins, and therapeutic methods based thereon
US5877217A (en) * 1995-12-26 1999-03-02 Alteon Inc. N-acylaminoalkyl-hydrazinecarboximidamides
US6110968A (en) * 1995-12-26 2000-08-29 The Picower Institute For Medical Research Methods for treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts
US20050134675A1 (en) * 2003-12-22 2005-06-23 Canon Kabushiki Kaisha Method of discriminating type of recording medium
US20170355669A1 (en) * 2010-05-11 2017-12-14 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents

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Publication number Priority date Publication date Assignee Title
US1672029A (en) * 1924-08-05 1928-06-05 C A F Kahlbaum Chem Fab G M B Process for the production of amidoguanidines and their alkyl derivatives
CH342957A (de) * 1958-06-10 1959-12-15 Ciba Geigy Verfahren zur Herstellung einer neuen Guanidinverbindung
DE1107215B (de) * 1958-06-20 1961-05-25 Geigy Ag J R Verfahren zur Herstellung von biociden Guanidinverbindungen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1672029A (en) * 1924-08-05 1928-06-05 C A F Kahlbaum Chem Fab G M B Process for the production of amidoguanidines and their alkyl derivatives
CH342957A (de) * 1958-06-10 1959-12-15 Ciba Geigy Verfahren zur Herstellung einer neuen Guanidinverbindung
DE1107215B (de) * 1958-06-20 1961-05-25 Geigy Ag J R Verfahren zur Herstellung von biociden Guanidinverbindungen

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3409669A (en) * 1963-12-13 1968-11-05 Evans Medical Ltd 2-(cyclohexylamino)-2-methyl-propylguanidine-1 and the salts and hydrate thereof
US3412105A (en) * 1966-01-05 1968-11-19 American Home Prod beta-aryl-n-guanidino-beta-alanines
US3454640A (en) * 1966-07-25 1969-07-08 Abbott Lab Alkoxy- or alkylthio-alkyleneaminoalkylguanidines
US3546227A (en) * 1966-12-01 1970-12-08 Sandoz Ag 2,3-dihydro-1h-benz(d,e)isoquinoline carboxamidines
US4271190A (en) * 1978-03-02 1981-06-02 Th. Goldschmidt Ag Guanidinium salts, processes for their manufacture as well as microbicidal preparations containing these compounds
EP0062844A1 (de) * 1981-04-09 1982-10-20 Beiersdorf Aktiengesellschaft Substituierte Benzo(de)isochinoline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US5612332A (en) * 1984-03-19 1997-03-18 Alteon Inc. Di- and triaminoguanidines, and methods of use
US5852009A (en) * 1984-03-19 1998-12-22 The Rockefeller University Compositions, including pharmaceutical compositions, for inhibiting the advanced glycosylation of proteins, and therapeutic methods based thereon
US6114323A (en) * 1984-03-19 2000-09-05 The Rockefeller University Methods for inhibiting the advanced glycosylation of proteins
US5850840A (en) * 1995-11-15 1998-12-22 Alteon Inc. Methods for measurement and treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts
US5877217A (en) * 1995-12-26 1999-03-02 Alteon Inc. N-acylaminoalkyl-hydrazinecarboximidamides
US6110968A (en) * 1995-12-26 2000-08-29 The Picower Institute For Medical Research Methods for treatment predicated on the presence of advanced glycosylation endproducts in tobacco and its combustion byproducts
US20050134675A1 (en) * 2003-12-22 2005-06-23 Canon Kabushiki Kaisha Method of discriminating type of recording medium
US20170355669A1 (en) * 2010-05-11 2017-12-14 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US11174223B2 (en) * 2010-05-11 2021-11-16 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents

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