US3821301A - Substituted aminoalkyl guanidines - Google Patents

Substituted aminoalkyl guanidines Download PDF

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Publication number
US3821301A
US3821301A US00302411A US30241172A US3821301A US 3821301 A US3821301 A US 3821301A US 00302411 A US00302411 A US 00302411A US 30241172 A US30241172 A US 30241172A US 3821301 A US3821301 A US 3821301A
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group
hydroxy
acid
grams
compounds
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US00302411A
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K Klingler
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DEUTSCHE GOLD und SILBER SCHEIDEANSTALT DT
Evonik Operations GmbH
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Degussa GmbH
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    • 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
    • C07C279/12—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 nitrogen atoms not being part of nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • R1 NH where R, is hydrogen or hydroxy, R is hydroxy, hydroxymethyl or alkyl or one to six carbon atoms, R is hydrogen or alkylof one to four carbon atoms and Alk is a straight or branched chain alkylene group of two to six carbon atoms and their acid addition salts, e.g., the acid addition salts with pharmacologically acceptable acids, i.e., pharmaceutically acceptable acids.
  • the compounds of the invention are pharmacologically active. They especially have high broncholytical activity as well as favorable circulatory effects (for example coronary widening activity, positive inotropic activity). H
  • the substituent R is preferably in the 3 or 4 position of the phenyl nucleus. If there are two substituents they are preferably in the 3,4 or 3,5 positions of the, phenyl nucleus. ln the case where the R residue is an alkyl group, preferably it has one to four carbon atoms, such as for example methyl, ethyl, propyl, butyl, isopropyl or t-butyl. In the case where R is an alkyl group, it is pref erably methyl or ethyl.
  • Alk is for example ethylene, propylene or butylene which can be substituted with the same or different carbon atoms, especially methyl or ethyl.
  • Alk is propylene (trimethylene) which in a given case can have a methyl substituent.
  • R and R areboth hydroxy.
  • salts of the substituted aminoalkyl guanidines there can be prepared and employed salts of any nontoxic pharmacologically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric'acid, acetic acid, p-toluene sulfonic acid, propionic acid, succinic acid, maleic acid, malonic acid, fumaric acid, lactic acid, tartaric acid and citric acid.
  • any nontoxic pharmacologically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric'acid, acetic acid, p-toluene sulfonic acid, propionic acid, succinic acid, maleic acid, malonic acid, fumaric acid, lactic acid, tartaric acid and citric acid.
  • Examples of compounds within the invention include 2-[2-(3,4-dihydroxyphenyl) -2-hydroxyethylamino] ethyl guanidine, 3-[2-(3,4-dihydroxyphenyl)-2- hydroxyethylamino] -propyl guanidine, 2-[ l-methyl-Z- 3 ,4-dihydroxyphenyl )-2hydroxyethylamino] -ethyl guanidine, 3-[2-(3,5-dihydroxyphenyl)-2-hydroxyethylamino1-propyl guanidine, l-methyl- 3-[2 -(3,5- dihydroxyphenyl) -2-hydroxy-ethylamino]-propyl guanidine, 3-[2-(4-hydroxyphenyl) -2- hydroxyethylamino] -propyl guanidine, 3-[2-(3- hydroxy-4-hydroxymethyl) -2-hydroxyethylamino] l-e
  • propyl guanidine 3-[2-(4-tbutylphenyl) -2-hydroxyethylamino] propyl guanidine 3-[2-(3 -hydroxy-4-hexyl-phenyl) -2 hydroxyethylamino] l-ethylpropyl guanidine, 2-[l-ethyl-2-(3,4- dihydroxyphenyl) -2-hydroxy-ethylamino] -ethyl guanidine, 3-.[ 1-butyl-2-(3,5-dihydroxyphenyl) -2- hydroxyethyl-amino1 propyl guanidine, 2-[2-(2,6-
  • R R and R as well as Alk are as defined above 7 with a reagent which converts the amino group into a guanidine group, or
  • Alk is'as definedabove, or
  • the latter is the case if the amino group as well as, ina given case, the phenolic hydroxyl group also are protected by a benzyl group or a'carbobenzoxy group and. for example a keto group is hydrogenated.
  • the protective group is not split off during the reaction, a simple after treatment of the reaction product is necessary wherein then the splitting. off of the protective groups takes place, for example under the conditions given above.
  • protective groups for the amino groups there can be used, for example: the benzyl group, a-phenylethyl group, benzyl groups substituted in the benzene nucleus such as, for example, the p-bromo or pnitrobenzyl group,v the carbobenzoxy group, the carbobenzthio group, the trifluoroacetyl group, the phthalyl group, the trityl group, the p-toluenesulfonyl group and similar groups.
  • These same protective groups can be used for the phenolic hydroxyl groups; additionally there can be used simple acyl groups, as, for example, the acetyl group.
  • Process (a) can be carried out in solution or as a molten mixture at temperatures between 20 and 150C, in a given case under elevated pressure.
  • solvents there can be used, for example, water or organic solvents such as alcohols, e.g., methanol, ethanol, propanol, isopropanol, or butanol, benzene, toluene, xylene, dioxane, alcohol water mixtures.
  • reagents which convert an amino group into the guanidine group there can be used especially S-alkylisothioureas wherein the alkyl is preferably a straight or branched chain alkyl group having one to six carbon atoms, e.g., S-methyl isothiourea, S-ethyl isothiourea, S-propyl isothiourea,
  • S-butyl isothiourea Sf-t-b'utyl isothiourea and S-hexyl isothiourea, cyanamide or guanidine.
  • These compounds can be employed as the free base or in the form of the usual acid addition salts, e.g., sulfates, hydrochlorides, etc.
  • Process (b) canbe carried out with or without solvents, for example at temperatures between to -l00C.
  • solvents here can be used organic solvents such as alcohols, e.g., propyl alcohol or the otheralcohols set forth above, aromatic liquid hydrocarbons such as benzene, toluene and xylene, or dimethyl formamide, etc.
  • Process (c) is carried out suitably in a solvent or in suspension at temperatures between 0 and 100C.
  • solvents or suspending agents there can be used water, lower aliphatic alcohols, e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol, propyl alcohol or butyl alcohol, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, e.g., diethyl ether, dimethyl formamide, etc., as well as mixtures of the agents with each other.
  • the reduction takes place through catalytic hydrogenation.
  • catalysts there can be used the customary finely divided metal catalysts such as, for
  • noble metal catalysts platinum, palladium
  • nickel nickel
  • the catalysts can be added with or without carriers. There can be employed normal pressure or elevated pressure. If the phenolic hydroxyl groups or the secondary amino groups contain hydrogenolytically splittable groups as for example benzyl groups, then these protective groups are simultaneouslysplit off in the catalytic hydrogenation, if, for example, there ,is used a palladium catalyst.
  • the reduction of the keto group can also take place through other known reducing agents which reduce a keto group to the hydroxy group.
  • reducing agents are for example: nascent hydrogen (zinc/acid such as zincglacial acetic acid or zinc-hydrochloric acid-aluminum amalgam), metal hydrides or complex metal hydrides (such as Lil-l, Li Al H alkali borohydrides, e.g., sodium borohydride, sodium triethoxy aluminum hydride), aluminum alcoholates such as aluminum isopropylate/isopropanol (Meerwein Ponndorf process), etc.
  • nascent hydrogen such as zincglacial acetic acid or zinc-hydrochloric acid-aluminum amalgam
  • metal hydrides or complex metal hydrides such as Lil-l, Li Al H alkali borohydrides, e.g., sodium borohydride, sodium triethoxy aluminum hydride
  • aluminum alcoholates such as aluminum isopropylate/isoprop
  • lfR is the hydroxymethyl group under mild conditionsthere is obtained the end product of formula I where R is CH OH and by stronger conditions the end product where R is CH To obtain the CH OH group it is suitable towork at low or only slightly elevated temperature as well as at normal pressure and starting compounds employed as the base.
  • ketone with a reducing agent that only attacks the keto group, especially complex metal hydride (such as sodium borohydride or lithium aluminum hydride) and in a given case subsequently splitting off the protective groups by catalystic hydrogenation under mild conditions.
  • complex metal hydride such as sodium borohydride or lithium aluminum hydride
  • process (0) can also be carried out by directly hydrogenating the reaction product (Schiffs base) from a compound of the formula without previous isolation of the Schiffs base.
  • This reaction of a compound of formula V with a compound of formula V1 is generally carried out in a solvent such as water, lower aliphatic alcohols such as those specified above, e.g., ethyl alcohol, isopropyl alcohol, cyclic ethers such as dioxane, dimethyl formamide, etc. or mixtures of these agents at temperatures between 0 to C.
  • This condensation can be carried out from the beginning under the hydrogenation conditions.
  • the compounds can be converted in known manner into salts.
  • anions for the salts there can be used those previously known and therapeutically usable acids such as those set forth above, e.g., hydrochloric acid, hydrogen peroxide, sulfuric acid, acetic acid, ptoluene sulfonic acid, succinic acid, maleic acid, malonic acid, fumaric acid, lactic acid, tartaric acid, etc.
  • the free bases can be produced again from the salts of the compounds in customary manner, for example, by treatment of a solution in an organic solvent such as alcohols (e.g., methanol, ethanol, butanol) with soda or soda lye.
  • an organic solvent such as alcohols (e.g., methanol, ethanol, butanol) with soda or soda lye.
  • Those compounds which containasymmetric carbon atoms and which as a rule are obtained as racemates can be split in known manner, for example, by means of optically active isomers, into optically active acid.
  • optically active or diastereometric starting materials whereby there isobtained as the final product a corresponding pure optically active form or a diastereomer configuration.
  • stereoisomer racemates since they are present in the compounds produced two or more asymmetrical carbon atoms. Separation is possible in the customary manner, for example, by recrystallization.
  • the pharmaceutical compositions or medicaments can contain one or more of the compounds of the invention or mixtures of these with other pharmaceutically active materials.
  • the customary pharmaceutical carriers and assistants can be used for the production of pharmaceutical preparations.
  • the medicines can be used enterally, parenterally, orally or perlingually. Dispensing can take place in the form of tablets, capsules, pills, dragees, plugs, ointments, powders, liquids or aerosols.
  • X is chlorine or bromine with aminoalkyl guanidines of the formula
  • the primary amino group connected to the alkylene group is protected by a benzyl group.
  • This reaction can be carried out, for example, in a solvent such as a lower aliphatic alcohol, e.g., methyl alcohol, ethyl alcohol, isopropyl alcohol or propyl alcohol, or an aromatic hydrocarbon such as benzene, toluene or xylene, or in dioxane at a temperature between 0 and C. Unless otherwise indicated all parts and percentages are by weight.
  • EXAMPLE 1 2-[ 2-( 3,4-dihydroxyphenyl )-2-hydroxycthyl-amino l ethyl guanidinc hydroxyethyl]- l ,2-diaminoethane dihydrochloride were dissolved in water, made alkaline with soda lye and'shaken with chloroform. The base remaining after drying and distilling ofiof the chloroform was dissolved in 240 ml of ethanol and treated with a solution of 18.6 grams of S-methyl isothiourea sulfate. The mixture was heated at reflux with stirring for 12 hours, after cooling there were added 8 ml of 2 normal sulfuric acid and filtered with suction on the dext day.
  • the free base was made from N-[1-methyl-2-(3,4- dibenzyloxyphenyl )-2-hydroxyethyl] -1 ,2- diaminoethane dihydrochloride in a manner analogous to example 1.
  • grams of the free base were dissolved in 195 ml of ethanol and there was added a solution of 15.2 grams of S-methyl isothiourea sulfate in 39 m1 of water and the reaction solution heated at reflux for 16 hours.
  • the mixture was acidified with 10 ml of 10% sulfuric acid, filtered with suction, washed with ethanol and crystallized from dimethyl formamide with addition of activated carbon.
  • the product filtered off was heated again with ethanol, again filtered with suction and dried.
  • EXAMPLE 4 3-[2-( 3,5-dihydroxyphenyl )-2-hydroxy-ethylamino] propyl guanidine
  • a manner analogous to example 1 there were prepared 16.1 grams of 3-[2-(3,5-dibenzylphenyl)-2- hydroxyethylamino]-propyl guanidine sulfate having a melting point of 262-265C. from 20.7 grams of N-[ 2-( 3,5dibenzyloxyphenyl) -2-hydroxyethyl ]-l ,3- diaminopropane dihydrochloride and 1 1.6 grams of S methyl isothiourea sulfate.
  • the above described sulfate having a melting point of 262 to 265C. can be stirred with barium chloride in aqueous solution on the water bath, the precipitated BaSO filtered off and the solution evaporated in a vacuum. The residue was stirred with acetone and the precipitated dihydrochloride filtered off with suction.
  • This salt was hydrogenated in a mixture of two parts of ethanol and one part of water at 60C. with addition of palladium-activated carbon catalyst.
  • EXAMPLE 5 1-methyl-3-[2-( 3,5-dihydroxyphenyl )-2-hydroxyethylaminol-propyl guanidine 19.9 grams of l-(3,5-dibenzyloxyphenyl)-l-hydroxy- 2-bromoethane were added to 17.0 grams of 1,3- diaminobutane. The mixture was stirred for 1% hours at C., dissolved in benzene, extracted twice with water, dried with potassium carbonate, filtered and the benzene distilled off. The base remaining behind was dissolved in ml of ethanol, 9.8 grams of S-methyl isothiourea sulfate in 25 ml of water added and the mixture heated at reflux with stirring for 10 hours.
  • the compounds of the invention are suited for the production of pharmaceutical compositions and preparations.
  • the pharmaceutical compositions or drugs contain as the active material one or several ofthe compounds of the invention, in a given case in-admixture with other pharmacologically or pharmaceutically effective materials.
  • the production of the medicine can take place with the use of known and customary pharmaceutical carriers and diluents, as well as other customary assistants.
  • Such materials include gelatin, sucrose, pectin, starch. tylose, talc, lycopodium, silica, lactose, cellulose derivatives, micropulverized cellulose, stearates, e.g., methylstearate and glyceryl stearate, emulsifiers, vegetable oils, water, pharmaceutically compatible monoor polyvalent alcohols.
  • polyglycols such as glycerine, mannitol, sorbitol, pentaerythritol, ethyl alcohol, diethylene glycol, triethylene glycol, ethylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol 400, as well as derivatives of such alcohols and polyglycols, dimethyl sulfoxide, esters of saturated and unsaturated fatty acids with monoor polyvalent alcohols such as glycols, glycerine, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc., e.g.
  • esters of polyvalent alcohols can in a given case also be etherified, benzyl benzoate, dioxolane, glycerine formal, glycol furfural, dimethyl acetamide, lactamide, lactates. e.g., ethyl lactate, ethyl carbonate, etc.
  • preservatives for example ethylenediaminotetraacetic acid
  • antioxidants there can be used for example sodium metal bisulfite and ascorbic acid
  • preservatives there can be used for example sorbic acid, phydroxybenzoic acid esters, e.g., methyl phydroxybenzoate and ethyl p-hydroxybenzoate and similar materials.
  • the drugs can be used enterally, parenterally, orally, perlingually or in the form of sprays.
  • the compounds of the invention have a good bronchospasmolytic activity as exhibited, for example, on the isolated tracheal spiral of the guinea pig.
  • the bronchospasmolytic activity is comparable to that of the known drug orciprerlaline.
  • the dosage range for broncholytic activity is the same as for orciprenaline.
  • the compounds of the invention have utility in treating bronchial asthma, chronic asthmatic bronchitis, emphysema bronchitis with spasmic components and additional obstructive respiratory illnesses.
  • the compounds can be delivered in the form of tablets, capsules, pills, dragees, liquids, dusts or aerosols.
  • liquids there can be used oilyor aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions.
  • the preferred forms of use are tablets which contain between 1 and 50 mg. of active material or solutions which contain between O.l and 5% of active material.
  • the amount of active component of the invention can be used for example in an amount of 2 mg dispensed orally or 10 strokes of a 0.2% solution dispensed as an aerosol. These doses can be dispensed once or several times a day.
  • the acute toxicity of the compounds of the invention in the mouse is between 50 mg/kg and mg/kg.
  • the drugs can be used in human medicine or in veterinary medicine, e.g., to treat cats, dogs, horses, sheep, cattle, goats and pigs.
  • R is hydrogen or hydroxy
  • R is hydroxy, hydroxymethyl or alkyl of one to six carbon atoms
  • R is hydrogen or alkyl of one tofour carbon atoms
  • Alk is an alkylene group of two to six carbon atoms or a salt thereof of a pharmaceutically acceptable acid.
  • V the 3 position and R is in the 4 or 5 position.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US00302411A 1971-11-08 1972-10-31 Substituted aminoalkyl guanidines Expired - Lifetime US3821301A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
AT960671A AT316576B (de) 1971-11-08 1971-11-08 Verfahren zur Herstellung von neuen substituierten Aminoalkyl-guanidinen und ihren Säureadditionssalzen

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US (1) US3821301A (OSRAM)
JP (1) JPS5243827B2 (OSRAM)
AT (1) AT316576B (OSRAM)
BE (1) BE791013A (OSRAM)
CA (1) CA979925A (OSRAM)
CH (1) CH573903A5 (OSRAM)
DD (1) DD104292A5 (OSRAM)
DE (1) DE2254091C3 (OSRAM)
FR (1) FR2159365B1 (OSRAM)
GB (1) GB1398918A (OSRAM)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4317832A (en) * 1978-09-06 1982-03-02 Klingler Karl Heinz Indolyl and methylindolyl substituted aminoalkyl guanidines

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2656608B1 (fr) * 1989-12-28 1992-04-24 Roussel Uclaf Nouvelles polyamines benzoylees, leur procede de preparation et leur application comme fongicides.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4317832A (en) * 1978-09-06 1982-03-02 Klingler Karl Heinz Indolyl and methylindolyl substituted aminoalkyl guanidines

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Publication number Publication date
DE2254091C3 (de) 1982-04-22
BE791013A (fr) 1973-05-07
AT316576B (de) 1974-07-25
DD104292A5 (OSRAM) 1974-03-05
CH573903A5 (OSRAM) 1976-03-31
JPS4856640A (OSRAM) 1973-08-09
FR2159365A1 (OSRAM) 1973-06-22
DE2254091A1 (de) 1973-05-24
FR2159365B1 (OSRAM) 1975-06-20
CA979925A (en) 1975-12-16
GB1398918A (en) 1975-06-25
JPS5243827B2 (OSRAM) 1977-11-02
DE2254091B2 (de) 1981-07-23

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