Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
  • C07D235/26—Oxygen atoms

Definitions

• the present invention relates to new 4-hydroxy-2-benzimidazolinone derivatives, processes for their preparation and medicaments containing these compounds.
• the new compounds and their pharmacologically acceptable salts inhibit adrenergic ⁇ -receptors and are therefore suitable for the treatment or prophylaxis of cardiovascular diseases
• DE-OS 2700193 describes 4-hydroxy-2-benzimidazolinone derivatives with a ⁇ -blocking effect, the fused benzene ring of which is unsubstituted.
• the compounds of the general formula I contain an optically active carbon atom in the aminopropoxy side chain and can therefore occur in both a racemic and in two optically active forms.
• the subject of the present application are both the racemic forms and the optical isomers.
• the lower alkyl groups which appear in the definitions of the substituents R, R 1 and R 2 can contain 1 to 6, preferably 1 to 4, carbon atoms.
• the methyl, isopropyl and tert-butyl groups are preferred.
• the alkylene radical which can optionally be formed by the substituents R 1 and R 2 , contains 2 to 4 carbon atoms.
• the acyl groups R 3 can be acid residues of straight-chain or branched aliphatic carboxylic acids having 2 to 6 carbon atoms or aromatic carboxylic acids which are optionally substituted by halogen atoms, lower alkyl or lower alkoxy groups.
• the acetyl, pivaloyl and benzoyl radicals are preferred.
• the new compounds have a better ß-receptor-blocking rating compared to the prior art and to commercial products of similar constitution and action.
• the DE 250 was determined on awake rabbits, ie the dose of the ⁇ -blocker at which the heart rate only decreased to 250 beats / min after prior injection of isoprenaline. rise.
• Y 1 and Y 2 in compounds of the general formula V represent all radicals which can react with the two primary amino groups in compounds of the general formula IV to form the imidhzoline ring.
• Such radicals are preferably halogen atoms, such as bromine or chlorine, amino, imidazolyl, lower alkoxy, lower acyloxy and phenoxy groups.
• carbonyl halides urea, N, N'-carbonyldiimidazole can be used as compounds of the general formula V.
• the processes according to the invention are advantageously carried out in a solvent which is inert under the reaction conditions, for. Water, ethanol, dioxane or dimethylformamide, optionally carried out in the presence of an acid-binding agent.
• the reactions can also be achieved after mixing the reaction components without a solvent.
• the reactions are carried out by standing at room temperature or by heating, if appropriate under a protective gas atmosphere.
• the compounds of general formula IV can be prepared, for example, by compounds of general formula VIII in which R 1 , R 2 ' U and V have the meaning given above, while G represents the amino or nitro group, reacted with compounds of the general formula III analogously to process a) and the substances thus obtained reduced.
• the reduction is carried out in a manner known per se, preferably by catalytic hydrogenation.
• the resulting crude o-phenylenediamine derivatives of the general formula IV are advantageously used as starting materials in process b) without further purification as mineral acid salts.
• the compounds of the general formula VIII are either substances described or can be easily prepared from substances described by known methods.
• the optional subsequent acylation of compounds of general formula I in which R 3 represents a hydrogen atom can be carried out in a conventional manner by reaction with a reactive acid derivative, e.g. B. acid halide, acid azide or acid anhydride, optionally in the presence of an acid-binding agent, for. B. pyridine in a solvent, e.g. B. acetone, benzene, dimethylformamide, or in excess acid.
• a reactive acid derivative e.g. B. acid halide, acid azide or acid anhydride
• an acid-binding agent for. B. pyridine
• a solvent e.g. B. acetone, benzene, dimethylformamide, or in excess acid.
• the compounds of the formula I according to the invention can be obtained in the form of a racemic mixture.
• the racemate is separated into the optically active forms by methods known per se via the diastereomeric salts of active acids, such as. B. tartaric acid, malic acid or camphorsulfonic acid.
• the new compounds of general formula I are obtained under the reaction conditions of the processes described predominantly as acid addition salts, for. B. as hydrochloride, and can be easily converted into the free bases by the methods described.
• an organic solvent with the equivalent amount of an inorganic or organic acid, e.g. As hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid.
• an inorganic or organic acid e.g. As hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid.
• the substances I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as, for. B. olive oil, suspended or dissolved.
• the new substances 1 according to the invention and their salts can be administered enterally or parenterally in liquid or solid form.
• Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers or buffers.
• additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation.
• Solid carriers are e.g. B.
• Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
• the invention is illustrated by the following examples. They show some of the numerous possible process variants that can be used for the synthesis of the compounds according to the invention. However, they do not represent a restriction of the subject matter of the invention.
• Phosgene is passed into a solution of 5.8 g of 2,3-diamino-1- (2-hydroxy-3-tert-butylaminopropoxy) -5-methyl-benzene-trihydrochloride in 150 ml of water in a moderate stream for about 30 minutes. After flushing with nitrogen, the mixture is evaporated to dryness and 3.04 g (61% of theory) of the title compound of mp 280-281 ° C. (as hydrochloride) is crystallized from ethanol.
• the diamine used as an intermediate is converted into 2- [2-hydroxy-3- (2-propylamino) by reacting the 2- (2,3-epoxypropoxy) -4-methyl-6-nitroaniline described in Example 1 with 2-propylamine ) -propoxy] -4-methyl-6-nitroaniline and subsequent catalytic hydrogenation.
• the diamine used as an intermediate is converted into 2,3-dinitro-1- [2,3-dinitro-1- (2,3-epoxypropoxy) -4-methyl-benzene with 2-propylamine by reaction of the 2,3-dinitro-1- 2-hydroxy-3- (2-propylamino) -propoxy] -4-methylbenzene, mp 122-124 ° C. and subsequent catalytic hydrogenation.
• the title compound is obtained as a hydrochloride with a decomposition point above 300 ° C. from 5-tert-butyl-2,3-diamino-1- (2-hydroxy-3-tert-butylamino-propoxy) -benzene- trihydrochloride.
• Phosgene is introduced into the aqueous solution of 7.2 g of 2,3-diamino-4,5-dimethyl-1- (2-hydroxy-3-tert-butylamino-propoxy) -benzene-trihydrochloride as described in the previous examples.
• the residue obtained after concentration is recrystallized from 30 ml of ethanol with the addition of activated carbon.
• After adding 20 ml of ethyl acetate, 1.1 g (17% of theory) of the title compound of mp 308-310 ° C. (as hydrochloride) are obtained.
• the above compound is converted into the sodium salt with methanolic sodium methylate. This is reacted in dioxane / dimethylformamide with excess 3-chloro-1,2-epoxypropane at 75 ° C. After concentration, the residue is taken up in chloroform, treated with water and activated carbon and freed from the solvent.
• the diamino compound required as an intermediate is obtained by reacting 2-amino-4,5-dimethyl-1- (2,3-epoxypropoxy) -3-nitrobenzene (Example 8) with 2-propylamine in boiling ethanol and subsequent catalytic hydrogenation receive.
• Example 6 Analogously to the process described in Example 6, the title compound is obtained as the hydrochloride from the decomposition point above 280 ° C. from 4,5-diamino-6- (2-hydroxy-3-tert-butylamino-propoxy) indane trihydrochloride.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Cardiology (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Citations (3)

• 1978
  • 1978-07-31 CA CA308,433A patent/CA1108619A/fr not_active Expired
  • 1978-08-08 ES ES472435A patent/ES472435A1/es not_active Expired
  • 1978-08-08 IL IL7855315A patent/IL55315A0/xx unknown
  • 1978-08-08 PT PT68404A patent/PT68404A/pt unknown
  • 1978-08-09 IT IT7826640A patent/IT7826640A0/it unknown
  • 1978-08-09 DE DE7878100633T patent/DE2860981D1/de not_active Expired
  • 1978-08-09 EP EP78100633A patent/EP0000784B1/fr not_active Expired
  • 1978-08-09 DD DD78207192A patent/DD137584A5/xx unknown
  • 1978-08-10 AT AT0582978A patent/AT364831B/de not_active IP Right Cessation
  • 1978-08-10 FI FI782452A patent/FI782452A/fi not_active Application Discontinuation
  • 1978-08-11 JP JP9811278A patent/JPS5432467A/ja active Pending
  • 1978-08-11 DK DK355378A patent/DK355378A/da not_active Application Discontinuation
  • 1978-08-14 AU AU38885/78A patent/AU3888578A/en active Pending
• 1980
  • 1980-07-18 US US06/171,940 patent/US4367235A/en not_active Expired - Lifetime

Patent Citations (3)

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