[go: up one dir, main page]

US3056789A - 3-quinolyl-guanidines - Google Patents

3-quinolyl-guanidines Download PDF

Info

Publication number
US3056789A
US3056789A US39234A US3923460A US3056789A US 3056789 A US3056789 A US 3056789A US 39234 A US39234 A US 39234A US 3923460 A US3923460 A US 3923460A US 3056789 A US3056789 A US 3056789A
Authority
US
United States
Prior art keywords
acid
methyl
salts
quinoline
guanido
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US39234A
Inventor
Urech Ernst
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF Corp
Novartis Corp
Original Assignee
Ciba Geigy Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba Geigy Corp filed Critical Ciba Geigy Corp
Application granted granted Critical
Publication of US3056789A publication Critical patent/US3056789A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the quinoline nucleus of these compounds may contain one or more identical or different substituents.
  • substituents are, for example lower alkyl, such as methyl, ethyl, n-propyl or iso-propyl, n-butyl, secondary or tertiary butyl, the hydroxyl group etherified hydroxyl, such as lower alkoxy, for example methoxy, ethoxy, n-propoxy, n-butoxy, lower alkylenedioxy, such as methylenedioxy, esterified hydroxyl, such as lower alkoxy-carbonyloxy, for example methoxy or ethoxy-carbonyloxy, lower alkanoyloxy, such as acetoxy or propionyloxy, mercapto, etherified mercapto, especially lower alkylmercapto, such as methyl or ethyl mercapto, carboxy, esterified carboxy, such as carbo-lower alkoxy, for example carbome
  • the guanido group is preferably unsubstituted. It can also however be substituted by hydrocarbon radicals, especially lower alkyl groups, such as methyl or ethyl, and/or an ethylene radical and/or an acyl radical.
  • hydrocarbon radicals especially lower alkyl groups, such as methyl or ethyl, and/or an ethylene radical and/or an acyl radical.
  • the substituent is an ethylene radical
  • the guanido group is a 4:S-dihydro-imidazolyl-(2)-amino group.
  • Acyl substituents of the guanido group are more particularly those of lower aliphatic or monocyclic aromatic, heterocyclic, araliphatic or heterocyclic-aliphatic carboxylic acids, for example lower alkoxy-carbonic acids, such as methoxy or ethoxy-carbonic acid, carbamic acids, for example NzN-di-lower alkyl-carbamic acids, such as NzN-dimethyl-carbamic acid, or N-aryl-carbamic acids, for example N-phenylcarbamic acid, lower alkanecarboxylic acids, such as acetic, propionic or pivalic acid, lower alkene-carboxylic acids, such as acrylic acid, lower alkine-carboxylic acids, such as propiolic acid, substituted aliphatic carboxylic acids, for example [3-cyclopentyl-propionic acid, monochloracetic acid or monobromacetic acid, trifluoracetic acid or methoxyacetic acid
  • Salts of the new compounds are above all those with therapeutically useful acids, such as inorganic acids, such as hydrochloric acid or hydrobromic acid, or perchloric acid, nitric acid or thiocyanic acid, sulfuric or phosphoric acids, or organic acids such as formic acid, acetic acid, propionic acid, glycollic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fu
  • therapeutically useful acids such as inorganic acids, such as hydrochloric acid or hydrobromic acid, or perchloric acid, nitric acid or thiocyanic acid, sulfuric or phosphoric acids, or organic acids such as formic acid, acetic acid, propionic acid, glycollic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fu
  • maric acid malic acid, tartaric acid, citric acid, ascorbic acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, Z-phenoxybenzoic acid, 2-acetoxy-benzoic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, para-toluene-sulfonic acid, naphthalenesulfonic acid or sulfamyl acids, or methionine, tryptophane, lysine or arginine.
  • Quaternary ammonium compounds are especially those which are formed by reaction with reactive esters of lower alkanols or aralkanols, for example lower alkyl-halides or aralkyl-halides, such as methyl, ethyl or benzyl chloride, bromide or iodide. From these addition products the ammonium hydroxides can be liberated which can be reacted with the other, above-described therapeutically useful inorganic or organic acids to form other quaternary ammonium salts.
  • reactive esters of lower alkanols or aralkanols for example lower alkyl-halides or aralkyl-halides, such as methyl, ethyl or benzyl chloride, bromide or iodide. From these addition products the ammonium hydroxides can be liberated which can be reacted with the other, above-described therapeutically useful inorganic or organic acids to form other quaternary ammonium salts.
  • the new quinoline compounds and their salts have a strong and long-lasting antihypertensive effect; they can therefore be used in cases of high blood pressure, particularly in neurogenic, renal or essential hypertension.
  • the new compounds are intended to be used as medicaments in the form of pharmaceutical preparations which contain said compounds in admixture with an organic or inorganic, solid or liquid pharmaceutical excipient suitable for enteral, for example oral or parenteral, administration.
  • Suitable excipients are substances that do not react with the new compounds such, for example, as water, gelatinc, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, White petroleum jelly, cholesterol and other known medicinal excipients.
  • the pharmaceutical preparations may be, for example, tablets, dragees, capsules or in liquid form solutions, suspensions or emulsions. They may be sterilized and/ or contain assistants such as preserving stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers. They may further contain other therapeutically useful substances.
  • the new compounds can be obtained by reacting in a manner known per se a 3-amino-quinoline or its salts with an S-lower alkyl-isothiourea or a cyanamide or a salt thereof, and if desired, in a resulting quinolyl-(3)-guanidine whose imino and/ or amino groups are unsubstituted the latter are substituted by hydrocarbon radicals or acyl radicals and/ or resulting salts are converted into the free compounds or resulting free compounds into salts.
  • the S-lower alkyl-isothioureas or the cyanamides may be N- unsubstituted or substiuted, for example by aliphatic hydrocarbon radicals, especially lower alkyl groups, such as methyl or ethyl, or an ethylene radical and/or an acyl radical of an acid mentioned above.
  • Such compounds may be in free form or in the form of salts thereof, particularly salts of mineral acids, for example hydrochloric acid, hydrobromic acid, nitric acid or sulfuric acid may be used.
  • the amino group represents more especially a primary amino group, but also a secondary amino group, for example a lower alkylamino group, such as a methyl or ethylamino group.
  • the reaction of the 3-amino-quinolines or their salts with the etherified isothioureas or its salts is performed preferably in the presence of a diluent, the choice of which depends on the solubilities of the reactants.
  • Diluents or solvents are, for example, water, alkanols, such as methanol, ethanol, n-propanol or iso-propanol or tertiary butanol, ethers, such as dioxane or tetrahydrofuran, ketones such as acetone or methyl-ethyl-ketone, lower alkane-carboxylic acids, such as acetic or propionic acid,
  • reaction can be carried out at room temperature or, if necessary, at a raised temperature, for example at the boiling temperature of the reaction mixture, under atmospheric or superatmospheric pressure or in the presence of an inert gas, for example nitrogen.
  • a raised temperature for example at the boiling temperature of the reaction mixture, under atmospheric or superatmospheric pressure or in the presence of an inert gas, for example nitrogen.
  • the reaction with cyanamides is carried out, for example, by heating the mixture of the 3-amino-quinoline, especially an addition salt thereof, with a mineral acid, such as hydrochloric acid, hydrobromic acid or sulfuric acid, and the cyanamide, preferably in the presence of a solvent or diluent, for example a lower alkanol, such as ethanol, or an aqueous acid, such as hydrochloric acid, to the melting or boiling point of the reaction mixture.
  • a solvent or diluent for example a lower alkanol, such as ethanol, or an aqueous acid, such as hydrochloric acid
  • the acid addition salt of the amine may also be formed intermediarily during this procedure; the cyanamide too when sodium cyanamide or 1-nitroso-3-methyl-guanidine is used.
  • the starting materials used for these reactions may contain the substituents required for the above defined end products. They are known or can be prepared by a method known per se.
  • quinolyl-(3)-guanidines whose imino and/ or amino groups are unsubstituted the latter may be converted, if desired, into substituted imino and/ or amino groups.
  • the resulting quinolyl-(3)-guanidines or their salts can be converted in a manner known per se with an amine substituted by a hydrocarbon radical, such as methyl, ethyl or propylamine, or with ethylenediamine, whereby with the latter, guanidines, cyclicized through the ethylene chain, i.e. 2-amino-4:S-dihydro-imidazoles are obtained.
  • the guanido group can also be acylated, for example by treating the guanidine compound with a reactive functional derivative of a carboxylic acid, for example a halide, such as chloride, or the anhydride.
  • a reactive functional derivative of a carboxylic acid for example a halide, such as chloride, or the anhydride.
  • the reactants can be reacted in the presence of an inert diluent, for example a hydrocarbon, such as pentane, hexane, toluene or xylene, or a tertiary organic base, for example a liquid pyridine, such as pyridine or collidine, or in the absence of such, for example by heating with an acylating agent, advantageously acetic anhydride, alone, in an open or closed vessel under pressure.
  • an inert diluent for example a hydrocarbon, such as pentane, hexane, toluene or xy
  • the new guanidines are obtained in the form of the free bases or of their salts.
  • the salts can be converted into the free bases in the known manner, for example by treatment with a strongly basic agent, such as an alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, or with a strong anion exchange resin, such as a quaternary ammonium exchange resin.
  • a strongly basic agent such as an alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a strong anion exchange resin such as a quaternary ammonium exchange resin.
  • the free bases can be converted into acid addition salts, for example by reaction with an inorganic or organic acid, for example one of the acids mentioned above; if desired, this can be carried out in the presence of a solvent, such as an alcohol, for example methanol, ethanol, propanol or isopropanol, or of an ether, for example diethyl ether or a para-dioxane, or of an alkylalkanoate, for example ethyl acetate, or in a mixture of two or more such solvents, if desired in the presence of water.
  • Basic, neutral, acid or mixed salts may be obtained.
  • the new guanidines or salts thereof may also be converted into quaternary ammonium compounds, for example by reaction with reactive esters of lower alkanols or aralkanols, such as lower alkyl or aralkyl halides, for example methyl, ethyl or benzyl chloride, bromide or iodide, di-lower alkyl sulfates, such as dimethyl or diethyl sulfate, or lower alkyl esters of alkane or aryl sulfonic acids, such as methane, ethane or para-toluene-sulfouic acid methyl or ethyl ester.
  • reactive esters of lower alkanols or aralkanols such as lower alkyl or aralkyl halides, for example methyl, ethyl or benzyl chloride, bromide or iodide, di-lower alkyl sulf
  • Quaternization is advantageously carried out in the presence of a diluent, for example in a lower alkanol, such as methanol, ethanol, n-propanol or tertiary butanol, a lower alkanone, such as acetone or methyl-ethyl-ketone,
  • a diluent for example in a lower alkanol, such as methanol, ethanol, n-propanol or tertiary butanol, a lower alkanone, such as acetone or methyl-ethyl-ketone,
  • an acid amide such as formamide or dimethyl-formamide.
  • Resulting quaternary ammonium salts may be converted into the corresponding ammonium hydroxides, for example by treatment with an ion exchanger, by reacting the ammonium halide with moist silver oxide, the ammonium sulfate with barium hydroxide, or by electrodialysis. From the quaternary ammonium hydroxides other therapeutically useful ammonium salts may be prepared with the previously mentioned acids.
  • the present invention further includes any variant of the process in which an intermediate obtained at any stage of the process is used as starting material and the remaining step or steps are carried out, or in which the starting materials are formed in the course of the reaction, or are present in the form of their salts or quaternary ammonium derivatives or acyl compounds.
  • Example 1 A solution of 18 grams of B-aminoquinoline hydrochloride in 20 cc. of ethanol is refluxed at the boil for 3 hours with 4.2 grams of cyanamide. Another 4.2 grams of cyanamide are then added, and the whole is heated for a further 4 hours. When the solution is allowed to cool, 3-guanido-quinoline hydrochloride of the formula separates from it in colorless crystals. After having been recrystallized from ethanol or methanol, the compound melts at 228230 C. It is readily soluble in water.
  • cyanamide a filtered ethanolic suspension of an appropriate proportion of sodium cyanamide, treated while cooling with a calculated amount of concentrated hydrochloride, may be used.
  • N-[quinolyl-(3) ]-N'-methyl-guanidine hydrochloride is obtained.
  • Other N-substituted compounds can be prepared in an identical manner.
  • the above 3-aminoquinoline hydrochloride can be replaced by a substituted 3-aminoquinoline hydrochloride whose benzene or pyridine nucleus contains for example an alkyl, such as methyl group, or alkoxy such as a methoxy group.
  • Example 2 9.7 grams of 3-methylamino-quinoline hydrochloride (obtained by heating an ethanolic solution of 3-bromoquinoline and methylamine in a tube at 150 C. in the presence of copper and converting the resulting base of M.P. C. into the hydrochloride), 5 grams of cyanamide and 20 cc. of ethanol are heated at the boil for 10 hours. The resulting solution is evaporated to dryness, and the residue is tr iturated with acetone. The remaining, undissolved portion is recrystallized from ethanol, to yield N-[quinolyl-(3)]-N-methyl-guanidine hydrochloride of the formula in colorless crystals melting at 237-239 C., which is readily soluble in water. The corresponding nitrate on the other hand, is sparingly soluble in water.
  • N-substituted compounds are obtained, such as N-[quinolyl-(3)]-N:N- dimethyl-guanidine hydrochloride.
  • N-substituted or N-substituted 3-guanidoquinolines can be prepared in a similar manner.
  • Example 3 A mixture of 7.2 grams of 3-aminoquinoline, grams of S-ethyl-isothiourea hydrobromide and 25 cc. of butanol is heated at the boil for several hours. After cooling, the separated crystals are suctioned off and washed with butanol. The mother liquor is evaporated and the residue treated with acetone, to yield a further amount of the same crystals, which are recrystallized from a small amount of hot water. In this manner 3-guanido-quinoline hydrobromide, decomposing at 218-220 C., is obtained, when it is treated with sodium nitrate it yields the corresponding nitrate melting at 238-240 C.
  • the S-ethyl-isothiourea hydrobromide may be replaced by another salt, such as the hydrochloride or hydriodide or another isothiourea ether.
  • 3-aminoquino1ine can also be reacted with S-ethyl-N- methyl-isothiourea hydrobromide, to yield N-[quinolyl- (3) ]-N'-methyl guanidine hydrobromide.
  • Example 4 A solution of 22.2 grams of 3-guanido-quinoline hydrochloride and 7.0 grams of ethylenediamine in 100 cc. of nbutanol is refluxed at the boil for 18 hours. On completion of the reaction the solution is cooled in ice. The separated crystals are suctioned oil and washed with butanol. Recrystallization from water or methanol yields 3- [N: N'-ethylene-guanido-(N") -quinoline hydrochloride of the formula in colorless crystals melting at 270-271 C. with decomposition. (For the melting point test the product is introduced into the apparatus at 250 C.) The new compound is water-soluble.
  • Example 5 A mixture of 16.0 grams of S-aminoquinoline, 24.4 grams of S-methyl-ethylene isothiourea hydriodide and 10 cc. of n-amyl alcohol is refluxed for 8-12 hours in an oil bath at 135-150" C., whereby methyl mercaptan is their quaternary lower alkyl ammonium halides and hydroxides, their quaternary benzyl ammonium halides and hydroxides and their therapeutically acceptable acid addition salts, in which formula Qu stands for a member selected from the group consisting of quinolyl-(3), lower alkyl-qninolyl-(Zi), lower alkoxy-quinolyl-(3), and R and R stand for a member selected from the group consisting of lower alkyl and hydrogen.
  • formula Qu stands for a member selected from the group consisting of quinolyl-(3), lower alkyl-qninolyl-(Zi), lower alkoxy-quinolyl-(3)

Landscapes

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

Description

United States Patent Ofifice 3,056,789 Patented Oct. 2, 1962 3,056,789 3-QUlNOLYL-GUANIDINES Ernst Urech, Biuuingen, Switzerland, assignor to Ciba (lorporation, a corporation of Delaware No Drawing. Filed June 28, 1960, Ser. No. 39,234 Claims priority, application Switzerland July 3, 1959 Claims. il. 260-286) The present invention relates to new quinoline compounds which contain a guanido group in the 3-position, their acyl derivatives, quaternary ammonium compounds and their salts and a process for the manufacture thereof.
The quinoline nucleus of these compounds may contain one or more identical or different substituents. Such substituents are, for example lower alkyl, such as methyl, ethyl, n-propyl or iso-propyl, n-butyl, secondary or tertiary butyl, the hydroxyl group etherified hydroxyl, such as lower alkoxy, for example methoxy, ethoxy, n-propoxy, n-butoxy, lower alkylenedioxy, such as methylenedioxy, esterified hydroxyl, such as lower alkoxy-carbonyloxy, for example methoxy or ethoxy-carbonyloxy, lower alkanoyloxy, such as acetoxy or propionyloxy, mercapto, etherified mercapto, especially lower alkylmercapto, such as methyl or ethyl mercapto, carboxy, esterified carboxy, such as carbo-lower alkoxy, for example carbomethoxy or carbethoxy, nitro, free amino, mono-substituted amino, for example lower alkylamino, such as methylor ethylamino, particularly disubstituted amino, for example dilower alkylamino, such as dimethylamino or diethylamino, halogen, such as fluorine, chlorine or bromine, or halogen-lower alkyl, such as trifluoromethyl.
In the new compounds the guanido group is preferably unsubstituted. It can also however be substituted by hydrocarbon radicals, especially lower alkyl groups, such as methyl or ethyl, and/or an ethylene radical and/or an acyl radical. When the substituent is an ethylene radical, the guanido group is a 4:S-dihydro-imidazolyl-(2)-amino group. Acyl substituents of the guanido group are more particularly those of lower aliphatic or monocyclic aromatic, heterocyclic, araliphatic or heterocyclic-aliphatic carboxylic acids, for example lower alkoxy-carbonic acids, such as methoxy or ethoxy-carbonic acid, carbamic acids, for example NzN-di-lower alkyl-carbamic acids, such as NzN-dimethyl-carbamic acid, or N-aryl-carbamic acids, for example N-phenylcarbamic acid, lower alkanecarboxylic acids, such as acetic, propionic or pivalic acid, lower alkene-carboxylic acids, such as acrylic acid, lower alkine-carboxylic acids, such as propiolic acid, substituted aliphatic carboxylic acids, for example [3-cyclopentyl-propionic acid, monochloracetic acid or monobromacetic acid, trifluoracetic acid or methoxyacetic acid, dimethylaminoacetic acid, B-diethylamine-propionic acid, B-piperidino-propionic acid or benzoic acid, para-methoxy-benzoic acid, 3:4:5-trimethoxy-benzoic acid, 4-O-ethoxy-carbonyl-syringic acid, 3,4-dichloro-benzoic acid, B-nitrobenzoic acid, 3-dimethylamino-benzoic acid or nicotinic acid, isonicotinic acid, Z-furan-carboxylic acid, Z-thiophenecarboxylic acid or phenylacetic acid, diphenylacetic acid, fi-phenyl-propionic acid, para-methoxy-phenylacetic acid, cinnamic acid, para-chloro-cinnamic acid, 3:4:5-trimethoxy-cinnamic acid or pyridyl-(2)-acetic acid or thienyl- (2)-acetic acid.
Salts of the new compounds are above all those with therapeutically useful acids, such as inorganic acids, such as hydrochloric acid or hydrobromic acid, or perchloric acid, nitric acid or thiocyanic acid, sulfuric or phosphoric acids, or organic acids such as formic acid, acetic acid, propionic acid, glycollic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fu
maric acid, malic acid, tartaric acid, citric acid, ascorbic acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenylacetic acid, 4-aminobenzoic acid, 4-hydroxybenzoic acid, anthranilic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, Z-phenoxybenzoic acid, 2-acetoxy-benzoic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, para-toluene-sulfonic acid, naphthalenesulfonic acid or sulfamyl acids, or methionine, tryptophane, lysine or arginine.
Quaternary ammonium compounds are especially those which are formed by reaction with reactive esters of lower alkanols or aralkanols, for example lower alkyl-halides or aralkyl-halides, such as methyl, ethyl or benzyl chloride, bromide or iodide. From these addition products the ammonium hydroxides can be liberated which can be reacted with the other, above-described therapeutically useful inorganic or organic acids to form other quaternary ammonium salts.
The new quinoline compounds and their salts have a strong and long-lasting antihypertensive effect; they can therefore be used in cases of high blood pressure, particularly in neurogenic, renal or essential hypertension.
An outstanding effect is shown, for example, by 3-guanido quinoline or 3 [NzN' ethylene-guanido-(N") quinoline and their physiologically tolerable acid addition salts.
The new compounds are intended to be used as medicaments in the form of pharmaceutical preparations which contain said compounds in admixture with an organic or inorganic, solid or liquid pharmaceutical excipient suitable for enteral, for example oral or parenteral, administration. Suitable excipients are substances that do not react with the new compounds such, for example, as water, gelatinc, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, White petroleum jelly, cholesterol and other known medicinal excipients. The pharmaceutical preparations may be, for example, tablets, dragees, capsules or in liquid form solutions, suspensions or emulsions. They may be sterilized and/ or contain assistants such as preserving stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers. They may further contain other therapeutically useful substances.
The new compounds can be obtained by reacting in a manner known per se a 3-amino-quinoline or its salts with an S-lower alkyl-isothiourea or a cyanamide or a salt thereof, and if desired, in a resulting quinolyl-(3)-guanidine whose imino and/ or amino groups are unsubstituted the latter are substituted by hydrocarbon radicals or acyl radicals and/ or resulting salts are converted into the free compounds or resulting free compounds into salts. The S-lower alkyl-isothioureas or the cyanamides may be N- unsubstituted or substiuted, for example by aliphatic hydrocarbon radicals, especially lower alkyl groups, such as methyl or ethyl, or an ethylene radical and/or an acyl radical of an acid mentioned above. Such compounds may be in free form or in the form of salts thereof, particularly salts of mineral acids, for example hydrochloric acid, hydrobromic acid, nitric acid or sulfuric acid may be used. In the 3-amino-quinoline used as starting material the amino group represents more especially a primary amino group, but also a secondary amino group, for example a lower alkylamino group, such as a methyl or ethylamino group.
The reaction of the 3-amino-quinolines or their salts with the etherified isothioureas or its salts is performed preferably in the presence of a diluent, the choice of which depends on the solubilities of the reactants. Diluents or solvents are, for example, water, alkanols, such as methanol, ethanol, n-propanol or iso-propanol or tertiary butanol, ethers, such as dioxane or tetrahydrofuran, ketones such as acetone or methyl-ethyl-ketone, lower alkane-carboxylic acids, such as acetic or propionic acid,
or formamides, such as dimethylformamide. The reaction can be carried out at room temperature or, if necessary, at a raised temperature, for example at the boiling temperature of the reaction mixture, under atmospheric or superatmospheric pressure or in the presence of an inert gas, for example nitrogen.
The reaction with cyanamides is carried out, for example, by heating the mixture of the 3-amino-quinoline, especially an addition salt thereof, with a mineral acid, such as hydrochloric acid, hydrobromic acid or sulfuric acid, and the cyanamide, preferably in the presence of a solvent or diluent, for example a lower alkanol, such as ethanol, or an aqueous acid, such as hydrochloric acid, to the melting or boiling point of the reaction mixture. The acid addition salt of the amine may also be formed intermediarily during this procedure; the cyanamide too when sodium cyanamide or 1-nitroso-3-methyl-guanidine is used.
The starting materials used for these reactions may contain the substituents required for the above defined end products. They are known or can be prepared by a method known per se.
In resulting quinolyl-(3)-guanidines whose imino and/ or amino groups are unsubstituted the latter may be converted, if desired, into substituted imino and/ or amino groups. For example the resulting quinolyl-(3)-guanidines or their salts can be converted in a manner known per se with an amine substituted by a hydrocarbon radical, such as methyl, ethyl or propylamine, or with ethylenediamine, whereby with the latter, guanidines, cyclicized through the ethylene chain, i.e. 2-amino-4:S-dihydro-imidazoles are obtained. The guanido group can also be acylated, for example by treating the guanidine compound with a reactive functional derivative of a carboxylic acid, for example a halide, such as chloride, or the anhydride. The reactants can be reacted in the presence of an inert diluent, for example a hydrocarbon, such as pentane, hexane, toluene or xylene, or a tertiary organic base, for example a liquid pyridine, such as pyridine or collidine, or in the absence of such, for example by heating with an acylating agent, advantageously acetic anhydride, alone, in an open or closed vessel under pressure.
Depending on the reaction conditions employed, the new guanidines are obtained in the form of the free bases or of their salts. The salts can be converted into the free bases in the known manner, for example by treatment with a strongly basic agent, such as an alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, or with a strong anion exchange resin, such as a quaternary ammonium exchange resin. The free bases, on the other hand, can be converted into acid addition salts, for example by reaction with an inorganic or organic acid, for example one of the acids mentioned above; if desired, this can be carried out in the presence of a solvent, such as an alcohol, for example methanol, ethanol, propanol or isopropanol, or of an ether, for example diethyl ether or a para-dioxane, or of an alkylalkanoate, for example ethyl acetate, or in a mixture of two or more such solvents, if desired in the presence of water. Basic, neutral, acid or mixed salts may be obtained.
The new guanidines or salts thereof may also be converted into quaternary ammonium compounds, for example by reaction with reactive esters of lower alkanols or aralkanols, such as lower alkyl or aralkyl halides, for example methyl, ethyl or benzyl chloride, bromide or iodide, di-lower alkyl sulfates, such as dimethyl or diethyl sulfate, or lower alkyl esters of alkane or aryl sulfonic acids, such as methane, ethane or para-toluene-sulfouic acid methyl or ethyl ester.
Quaternization is advantageously carried out in the presence of a diluent, for example in a lower alkanol, such as methanol, ethanol, n-propanol or tertiary butanol, a lower alkanone, such as acetone or methyl-ethyl-ketone,
4 or an acid amide, such as formamide or dimethyl-formamide.
Resulting quaternary ammonium salts may be converted into the corresponding ammonium hydroxides, for example by treatment with an ion exchanger, by reacting the ammonium halide with moist silver oxide, the ammonium sulfate with barium hydroxide, or by electrodialysis. From the quaternary ammonium hydroxides other therapeutically useful ammonium salts may be prepared with the previously mentioned acids.
The present invention further includes any variant of the process in which an intermediate obtained at any stage of the process is used as starting material and the remaining step or steps are carried out, or in which the starting materials are formed in the course of the reaction, or are present in the form of their salts or quaternary ammonium derivatives or acyl compounds.
The following examples illustrate the invention.
Example 1 A solution of 18 grams of B-aminoquinoline hydrochloride in 20 cc. of ethanol is refluxed at the boil for 3 hours with 4.2 grams of cyanamide. Another 4.2 grams of cyanamide are then added, and the whole is heated for a further 4 hours. When the solution is allowed to cool, 3-guanido-quinoline hydrochloride of the formula separates from it in colorless crystals. After having been recrystallized from ethanol or methanol, the compound melts at 228230 C. It is readily soluble in water.
Instead of cyanamide, a filtered ethanolic suspension of an appropriate proportion of sodium cyanamide, treated while cooling with a calculated amount of concentrated hydrochloride, may be used.
When methyl cyanamide is used instead of cyanamide, N-[quinolyl-(3) ]-N'-methyl-guanidine hydrochloride is obtained. Other N-substituted compounds can be prepared in an identical manner.
The above 3-aminoquinoline hydrochloride can be replaced by a substituted 3-aminoquinoline hydrochloride whose benzene or pyridine nucleus contains for example an alkyl, such as methyl group, or alkoxy such as a methoxy group.
Example 2 9.7 grams of 3-methylamino-quinoline hydrochloride (obtained by heating an ethanolic solution of 3-bromoquinoline and methylamine in a tube at 150 C. in the presence of copper and converting the resulting base of M.P. C. into the hydrochloride), 5 grams of cyanamide and 20 cc. of ethanol are heated at the boil for 10 hours. The resulting solution is evaporated to dryness, and the residue is tr iturated with acetone. The remaining, undissolved portion is recrystallized from ethanol, to yield N-[quinolyl-(3)]-N-methyl-guanidine hydrochloride of the formula in colorless crystals melting at 237-239 C., which is readily soluble in water. The corresponding nitrate on the other hand, is sparingly soluble in water.
When the cyanamide is replaced by a substituted cyanamide, such as methyl cyanamide, N-substituted compounds are obtained, such as N-[quinolyl-(3)]-N:N- dimethyl-guanidine hydrochloride.
Other N-substituted or N-substituted 3-guanidoquinolines can be prepared in a similar manner.
Example 3 A mixture of 7.2 grams of 3-aminoquinoline, grams of S-ethyl-isothiourea hydrobromide and 25 cc. of butanol is heated at the boil for several hours. After cooling, the separated crystals are suctioned off and washed with butanol. The mother liquor is evaporated and the residue treated with acetone, to yield a further amount of the same crystals, which are recrystallized from a small amount of hot water. In this manner 3-guanido-quinoline hydrobromide, decomposing at 218-220 C., is obtained, when it is treated with sodium nitrate it yields the corresponding nitrate melting at 238-240 C.
The S-ethyl-isothiourea hydrobromide may be replaced by another salt, such as the hydrochloride or hydriodide or another isothiourea ether.
3-aminoquino1ine can also be reacted with S-ethyl-N- methyl-isothiourea hydrobromide, to yield N-[quinolyl- (3) ]-N'-methyl guanidine hydrobromide.
Example 4 A solution of 22.2 grams of 3-guanido-quinoline hydrochloride and 7.0 grams of ethylenediamine in 100 cc. of nbutanol is refluxed at the boil for 18 hours. On completion of the reaction the solution is cooled in ice. The separated crystals are suctioned oil and washed with butanol. Recrystallization from water or methanol yields 3- [N: N'-ethylene-guanido-(N") -quinoline hydrochloride of the formula in colorless crystals melting at 270-271 C. with decomposition. (For the melting point test the product is introduced into the apparatus at 250 C.) The new compound is water-soluble.
Example 5 A mixture of 16.0 grams of S-aminoquinoline, 24.4 grams of S-methyl-ethylene isothiourea hydriodide and 10 cc. of n-amyl alcohol is refluxed for 8-12 hours in an oil bath at 135-150" C., whereby methyl mercaptan is their quaternary lower alkyl ammonium halides and hydroxides, their quaternary benzyl ammonium halides and hydroxides and their therapeutically acceptable acid addition salts, in which formula Qu stands for a member selected from the group consisting of quinolyl-(3), lower alkyl-qninolyl-(Zi), lower alkoxy-quinolyl-(3), and R and R stand for a member selected from the group consisting of lower alkyl and hydrogen.
2. 3-guanido-quinoline.
3. A therapeutically acceptable acid addition salt of B-guanido-quinoline.
4. 3- N-methyl-guanido- (N) -quinoline.
5. A therapeutically acceptable acid addition salt of 3- [N-methyl-guanido-( N) ]-quinoline.
6. B-[N-methyl-guanido-(N)]-quino1ine.
7. A therapeutically acceptable acid addition salt of 3- [N-methyl-guanido- (N) J-quinoline.
8. 3- [NxN'-dimethyl-guanido-(N) J-quinoline.
9. A therapeutically acceptable acid addition salt of 3- [N N-dimethyl-guanido- (N) ]-quinoline.
References Cited in the file of this patent Gulland et al.: J. Chem. Soc., London, pages 1257-59 (1949).
Chandron et al.: Journal of Scientific and Industrial Research, volume 11 (1952), pages 129-132.

Claims (1)

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF GUANIDINES OF THE FORMULA:
US39234A 1957-05-07 1960-06-28 3-quinolyl-guanidines Expired - Lifetime US3056789A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US889282XA 1957-05-07 1957-05-07
CH7526259 1959-07-03

Publications (1)

Publication Number Publication Date
US3056789A true US3056789A (en) 1962-10-02

Family

ID=88513709

Family Applications (1)

Application Number Title Priority Date Filing Date
US39234A Expired - Lifetime US3056789A (en) 1957-05-07 1960-06-28 3-quinolyl-guanidines

Country Status (2)

Country Link
US (1) US3056789A (en)
GB (1) GB889282A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3314963A (en) * 1962-07-23 1967-04-18 Pfizer & Co C Azabenzocycloalkane-n-carboxamidines
US3450818A (en) * 1965-04-22 1969-06-17 Murphy Chem Co Ltd The Simultaneously effective antifungal and insecticidal or acaricidal pesticides
US4293549A (en) * 1977-11-07 1981-10-06 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktion-Saktieselskab) Quinolinyl guanidines having antiinflammatory, analgesic or antipyretic activity
WO2013016178A1 (en) * 2011-07-25 2013-01-31 Allergan, Inc. N-(imidazolidin-2-ylidene)quinoline derivatives as modulators of alpha 2 adrenergic receptors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4211958A1 (en) * 1992-04-01 1993-10-21 Pharmpur Gmbh Treatment products for ophthalmology and its use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3314963A (en) * 1962-07-23 1967-04-18 Pfizer & Co C Azabenzocycloalkane-n-carboxamidines
US3450818A (en) * 1965-04-22 1969-06-17 Murphy Chem Co Ltd The Simultaneously effective antifungal and insecticidal or acaricidal pesticides
US4293549A (en) * 1977-11-07 1981-10-06 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktion-Saktieselskab) Quinolinyl guanidines having antiinflammatory, analgesic or antipyretic activity
WO2013016178A1 (en) * 2011-07-25 2013-01-31 Allergan, Inc. N-(imidazolidin-2-ylidene)quinoline derivatives as modulators of alpha 2 adrenergic receptors
US8815861B2 (en) 2011-07-25 2014-08-26 Allergan, Inc. N-(imidazolidin-2-ylidene)quinoline derivatives as modulators of alpha 2 adrenergic receptors
US9199989B2 (en) 2011-07-25 2015-12-01 Allergan, Inc. N—(imidazolidin-2-ylidene)quinoline derivatives as modulators of alpha 2 adrenergic receptors

Also Published As

Publication number Publication date
GB889282A (en) 1962-02-14

Similar Documents

Publication Publication Date Title
DE69427548T2 (en) Heterocyclic derivatives as platelet aggregation inhibitors
US3129225A (en) Novel 4-oxy-3-maleimidyl betaines
CA3013433A1 (en) Sulfonamide derivative and pharmaceutical composition containing same
US3056789A (en) 3-quinolyl-guanidines
CA2174649A1 (en) Prodrugs of an inhibitor of hiv protease
US3169966A (en) Aminopyrazoles
CH511867A (en) Hypotensive n-pyrazinoyl-ethyl-piperazines
US3060177A (en) O-(aminoalkyl)oxime derivatives of heterocyclic aldehydes and ketones
US2672460A (en) Disubstituted piperazines and methods of preparing the same
US3395146A (en) 4-substituted-2-benzhydryl-2-butanol derivatives
US4330550A (en) Oxoimidazolinealkanoic acids and their salts and esters, their preparation and pharmaceutical compositions containing them
US2935514A (en) Benzimidazoles
US4132795A (en) Benzenesulfonyl ureas and their use for the treatment of diabetes mellitus
US3919242A (en) 1-(Benzodioxanylalkylene)piperidines
US3299069A (en) 5-nitrothiazolyl oxo-diazacycloalkanes
US3682933A (en) Derivatives of benzoxazoline-2-one
US2987518A (en) Certain 1h [4, 5-c]-imidazopyridines
US3228946A (en) New aminopyrazoles
US3963735A (en) Acylated 2-aminothiazole derivatives
US3321484A (en) Pyridinecarboxylic acid esters of cyclobutanediols
US3674787A (en) 2-(alpha-morpholinobenzyl)-anilides
US3250764A (en) New anthranilic acid hydrazides
US2404199A (en) 2-sulphanilamido-quinoxaline
US3426017A (en) Sulfonylurea compounds
NO119270B (en)