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WO1986000522A1 - UTILISATION D'HYDRAZONES ET D'OXIMES D'ACIDES alpha-CETOCARBONIQUES EN CAS DE MALADIES CARDIAQUES ET CIRCULATOIRES - Google Patents

UTILISATION D'HYDRAZONES ET D'OXIMES D'ACIDES alpha-CETOCARBONIQUES EN CAS DE MALADIES CARDIAQUES ET CIRCULATOIRES Download PDF

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Publication number
WO1986000522A1
WO1986000522A1 PCT/EP1985/000338 EP8500338W WO8600522A1 WO 1986000522 A1 WO1986000522 A1 WO 1986000522A1 EP 8500338 W EP8500338 W EP 8500338W WO 8600522 A1 WO8600522 A1 WO 8600522A1
Authority
WO
WIPO (PCT)
Prior art keywords
propionic acid
group
acid
chain
halogen
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.)
Ceased
Application number
PCT/EP1985/000338
Other languages
German (de)
English (en)
Inventor
Hans KÜHNLE
Hans-Peter Wolff
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.)
Roche Diagnostics GmbH
Original Assignee
Boehringer Mannheim GmbH
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
Priority claimed from DE19843426221 external-priority patent/DE3426221A1/de
Priority claimed from DE19843426222 external-priority patent/DE3426222A1/de
Priority claimed from DE19843426223 external-priority patent/DE3426223A1/de
Priority claimed from DE19843426220 external-priority patent/DE3426220A1/de
Application filed by Boehringer Mannheim GmbH filed Critical Boehringer Mannheim GmbH
Priority to HU853678A priority Critical patent/HU197668B/hu
Publication of WO1986000522A1 publication Critical patent/WO1986000522A1/fr
Priority to DK79786A priority patent/DK79786D0/da
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)

Definitions

  • the present invention relates to new uses of compounds which are known per se for other indications in medicine.
  • some monoamine oxidase inhibitors e.g. B. phenelzine (2-phenylethyl-hydrazine) or mebanazine (1-phenylethyl-hydrazine) can be hypoglycaemic in high doses (Adnitt, PI: Hypoglycemic action of monoamino oxidase inhibitors, Diabetes 17: 628-633 [1968], Wickström, Petterson, K .: Treatment of diabetes with monoamino oxidase inhibitors, Lancet 2: 995-997 [1964], Cooper, AJ, Reddie, KMG: Hypotensive collapse and hypoglycaemia after mebanazine - a monoamine-oxidase inhibitor, Lancet 1: 1133-1135 [1964]).
  • the main effect is the inhibitory effect of monoamine oxidase (MAO), so that these compounds have found use in the therapy of mental illnesses (van Praag, HM, Leijnse, B .: The influence of some antidepressant drugs of the hydrazine type on the glucose metabolism in depressed patients, Clin. chim. Acta 8: 466-475 [1963]), but could not be used as antihypertensive drugs.
  • MAO monoamine oxidase
  • Y is an oxygen atom or an -NH group
  • Z is a straight-chain or branched, saturated or unsaturated alkylene group with up to 8 C atoms, which is optionally substituted one or more times by halogen or hydroxy,
  • R 1 is hydrogen, a C 1 -C 8 alkyl group which is optionally mono- or polysubstituted by halogen, hydroxyl, nitrile, phenyl or carboxyl, nitrile or formyl,
  • R 2 is a straight-chain or branched, saturated or unsaturated alkyl group having up to 14 C atoms, a C 1 -C 6 -alkoxy or C 1 -C 6 -alkylthio group which is optionally substituted by lower alkoxy, cycloalkyl or aryl, a C 3 - C 8 cycloalkyl group, phenylamino,
  • Phenyl-N-alkylamino, phenylmercapto, aryl or aryloxy can mean, the latter 5 substituents in the aryl part each optionally one or more times by C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halogen, trifluoromethyl, hydroxy, amino , Acetylamino, acetoxy, cyano, nitro or the methylenedioxy group can be substituted, as well as their physiologically acceptable salts, esters and amides.
  • FFA free fatty acids
  • long-chain and short-chain free fatty acids differ metabolically essentially in that long-chain fatty acids pass through the mitochondrial membrane with the aid of the carnitine acyl transferase system (see drawing), while short-chain fatty acids pass through the mitochondrial space without the aid of them Reach the reaction chain. It was therefore reasonable to assume that the compounds of the general formulas IV have their effect in terms of inhibiting CAT.
  • the livers of 48 h fasted guinea pigs were dissected out under anesthetic anesthesia and most of the connective tissue was removed. After dabbing briefly on filter paper, the organ was immediately transferred to 60 ml of preparation medium with the following composition:
  • the pH was adjusted to 7.45 using 20% KOH using an electronic pH meter.
  • the liver was then cut into small pieces with scissors and washed two to three times to remove the adhering blood residues.
  • the liver sections were then homogenized using a plotter and the homogenate was brought to a final volume of approximately 20 ml.
  • centrifugation was now carried out at 700 ⁇ g for 15 minutes, the supernatant was collected and centrifuged at 9,000 g for a further 15 minutes.
  • the precipitate was washed three times in the preparation medium and recentrifuged in each case.
  • the purified mitochondria so old were finally suspended in the paration medium. This mitochondrial suspension was used for all determinations.
  • the protein concentration is determined using the biuret method.
  • the CAT activity was determined in the direction of carnitine-C 14 formation from palmitoyl-carntitin-C 14 . Because of the known location of the CAT II on the inner mitochondrial membrane and the impassability of the same CoASH, it becomes clear that without the addition of this co-enzyme, only the CAT II has access to the inner mitochondrial CoASH pool. Under these conditions, only CAT II is measured with intact mitochondria.
  • the mitochondrial preparation is treated with ultrasound, or CoASH is added to the incubation medium, the sum of the activity of CAT I and CAT II is determined.
  • the incubation medium consisted of the following components (final concentration in the test):
  • the contents of the incubation tubes were then poured into small plastic centrifuge tubes and centrifuged in the cooling centrifuge at 4 x 10 3 RPM.
  • the compounds of the general formulas I to V are therefore suitable for the treatment of cardiovascular diseases.
  • diseases that are associated with an undersupply of oxygen (ischemia) of the heart such as in particular heart failure, angina pectoris and heart attack.
  • ischemia undersupply of oxygen
  • the present invention therefore relates to the new use of compounds of the general formulas I - V.
  • Cycloalkyl in the general formulas I, III, IV and V is preferably understood to mean cyclohexyl.
  • Aryl in the general formulas I, IV and V are understood to mean aromatic hydrocarbons having 6 to 14 carbon atoms, preferably the phenyl and naphthyl group, in particular phenyl.
  • Halogen in all cases is preferably fluorine, chlorine or bromine, especially chlorine.
  • the straight-chain or branched, saturated or unsaturated alkyl radicals of the substituents R 2 and R in the formulas I and III can contain 1-14 carbon atoms, the straight-chain, saturated alkyl radicals being the methyl, ethyl, propyl, butyl, pentyl , Hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl and tetradecyl radical come into question.
  • Preferred branched, saturated alkyl radicals are the isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, isohexyl, 2-ethylbutyl, 3,3-dimethyl-butyl, 1-methyl-hexyl, 4-methyl-hexyl, 5-methyl-hexyl, 2-ethyl-hexyl, 3,5-dimethyl-hexyl and 3-methyl-octyl radical.
  • Straight-chain or branched, unsaturated alkyl radicals in R 2 and R are preferably the allyl, 3-butenyl, 3-pentenyl, 2-, 3-, 4- or 5-hexenyl, 9- Decenyl, 2-methylallyl, 3,7-dimethyl-6-octenyl, 2-propynyl, 2-butynyl and 2-hexynyl radicals.
  • the alkyl group of the substituent R in formula IV is understood to mean straight-chain or branched, saturated or unsaturated hydrocarbon radicals having 1 to 5 carbon atoms. In this sense, the methyl, ethyl, propyl, allyl and methallyl radicals are preferred.
  • unbranched alkylene chains A are preferably understood to mean the following:
  • esters of the carboxylic acids of the general formula I are generally to be understood as the reaction products of the carboxylic acids with alcohols.
  • the lower monohydric alcohols such as methanol, ethanol, propanol or isopropanol are preferred as alcohol components.
  • the amides of the general formula I according to the invention contain as amine components, for. B. ammonia, mono- and dialkylamines, e.g. B. 2-hydroxyethylamine and 1-methyl-piperazine and amino acids, where p-aminobenzoic acid, anthranilic acid, phenylalanine, ⁇ - and ß-alanine, serine, valine, glycine, arginine and many more are to be mentioned.
  • amine components for. B. ammonia, mono- and dialkylamines, e.g. B. 2-hydroxyethylamine and 1-methyl-piperazine and amino acids, where p-aminobenzoic acid, anthranilic acid, phenylalanine, ⁇ - and ß-alanine, serine, valine, glycine, arginine and many more are to be mentioned.
  • Alkali, alkaline earth and ammonium salts are particularly suitable as physiologically acceptable salts.
  • the following compounds are particularly preferred for the purposes of the invention:
  • All conventional oral and parenteral administration forms are suitable as cardiovascular preparations according to the invention, for example tablets, capsules, dragees, syrups, solutions, suspensions, drops, suppositories etc.
  • Oral administration is preferred, but also i. v. -Application is conceivable, e.g. B. in a post-infarct treatment to prevent the enlargement of the heart attack.
  • the invention therefore also relates to medicaments containing compounds of the general formulas I-IV insofar as they are packaged for the new indication and in particular are provided with instructions for their use.
  • Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols).
  • Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols).
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, dissolving agents and / or buffers.
  • additives are e.g. B. acetate or tartrate buffer, ethanol, complexing agent (such as
  • Ethylenediamine-tetraacetic acid and its non-toxic salts or high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation.
  • high molecular weight polymers such as liquid polyethylene oxide
  • the dosage can depend on various factors, such as the mode of administration, species, age and / or individual conditions. In people with a body weight of approx. 70 kg, a dose of 20-700 mg / day, preferably 100-400 mg / day in 1-4 individual doses, is normally to be assumed. However, higher doses may be appropriate or smaller quantities may be justified for local application.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Nouvelle utilisation médicale d'hydrazones et d'oximes d'acides alpha-cétocarboniques de formule générale (I) où Y représente un atome d'oxygène ou un groupe -NH-; Z représente un groupe alkyle saturé ou non saturé, à chaîne droite ou ramifiée, avec jusqu'à 8 atomes de C, substitué le cas échéant une ou plusieurs fois par un halogène ou un hydroxy; R1 représente un hydrogène, un nitrile, un formyle ou un groupe alkyle comportant de 1 à 8 C substitué le cas échéant une ou plusieurs fois par un halogène, un hydroxy, un nitrile, un phénile ou un carboxyle. R2 représente un groupe alkyle saturé ou non saturé, à chaîne droite ou ramifiée, avec jusqu'à 14 atomes de C; un groupe alkoxy comportant de 1 à 6 C ou alkylthio comportant de 1 à 6 C substitué le cas échéant par un alkoxy inférieur, un cycloalkyle ou un aryle; un groupe cycloalkyle comportant de 3 à 8 C; un phénylamino; un phényl-N-alkylamino; un phénylmercapto; un aryle; ou un aryloxy; ces 5 derniers substituant dans la partie aryle pouvant être substitués une ou plusieurs fois le cas échéant par un alkyl comportant de 1 à 6 C, un alkoxy comportant de 1 à 6 C, un halogène, un trifluorométhyle, un hydroxy, un amino, un acétylamino, un acétoxy, un cyano, un nitro ou le groupe méthylènedioxy. Ainsi que leurs sels, esters et amides physiologiquement supportables pour la prophylaxie et/ou le traitement de maladies cardiaques et circulatoires, en particulier les maladies cardiaques ischémiques comme l'insuffisance cardiaque, l'angine de poitrine ou l'infarctus du myocarde.
PCT/EP1985/000338 1984-07-17 1985-07-11 UTILISATION D'HYDRAZONES ET D'OXIMES D'ACIDES alpha-CETOCARBONIQUES EN CAS DE MALADIES CARDIAQUES ET CIRCULATOIRES Ceased WO1986000522A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
HU853678A HU197668B (en) 1984-07-17 1985-07-11 Process for producing pharmaceutical compositions comprising alpha-ketocarboxylic acid hydrazines and oximes
DK79786A DK79786D0 (da) 1984-07-17 1986-02-20 Anvendelse af alfa-ketocarbonsyrehydrazoner og -oximer til hjerte- ogkredsloebssygdomme

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
DEP3426222.9 1984-07-17
DEP3426223.7 1984-07-17
DE19843426221 DE3426221A1 (de) 1984-07-17 1984-07-17 Verwendung von n-substituierten brenztraubensaeurehydrazonen zur prophylaxe und/oder behandlung von herz- und kreislauferkrankungen sowie entsprechende arzneimittel
DEP3426220.2 1984-07-17
DE19843426222 DE3426222A1 (de) 1984-07-17 1984-07-17 Verwendung von n-substituierten 2-hydrazono-propionsaeurederivaten zur prophylaxe und/oder behandlung von herz- und kreislauferkrankungen sowie entsprechende arzneimittel
DEP3426221.0 1984-07-17
DE19843426223 DE3426223A1 (de) 1984-07-17 1984-07-17 Verwendung von 2-(phenylalkylhydrazono)-propionsaeurederivaten zur prophylaxe und/oder behandlung von herz- und kreislauferkrankungen sowie entsprechende arzneimittel
DE19843426220 DE3426220A1 (de) 1984-07-17 1984-07-17 Verwendung von o-substituierten brenztraubensaeureoximen zur prophylaxe und/oder behandlung von herz- undkreislauferkrankungen sowie entsprechende arzneimittel

Publications (1)

Publication Number Publication Date
WO1986000522A1 true WO1986000522A1 (fr) 1986-01-30

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1985/000338 Ceased WO1986000522A1 (fr) 1984-07-17 1985-07-11 UTILISATION D'HYDRAZONES ET D'OXIMES D'ACIDES alpha-CETOCARBONIQUES EN CAS DE MALADIES CARDIAQUES ET CIRCULATOIRES

Country Status (6)

Country Link
EP (1) EP0298955A1 (fr)
AU (1) AU572331B2 (fr)
DK (1) DK79786D0 (fr)
HU (1) HU197668B (fr)
IL (1) IL75818A (fr)
WO (1) WO1986000522A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2365555A1 (fr) * 1976-09-25 1978-04-21 Boehringer Mannheim Gmbh Derives d'acide 2-(phenylalkylhydrazono)-propionique, procede pour leur preparation et medicaments contenant ces corps
EP0001144A1 (fr) * 1977-09-01 1979-03-21 Roche Diagnostics GmbH Dérivés N-substitués de l'acide 2-hydrazono-propionique, procédé pour leur préparation et médicaments les contenant
EP0046554A1 (fr) * 1980-08-23 1982-03-03 Roche Diagnostics GmbH Hydrazones N-substitués de l'acide pyruvique, procédés pour leur préparation et médicaments contenant ces composés
EP0048911A2 (fr) * 1980-09-26 1982-04-07 Roche Diagnostics GmbH Oximes o-substituées dérivées de l'acide alpha-cétocarboxylique, procédé de préparation et médicaments qui les contiennent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2365555A1 (fr) * 1976-09-25 1978-04-21 Boehringer Mannheim Gmbh Derives d'acide 2-(phenylalkylhydrazono)-propionique, procede pour leur preparation et medicaments contenant ces corps
EP0001144A1 (fr) * 1977-09-01 1979-03-21 Roche Diagnostics GmbH Dérivés N-substitués de l'acide 2-hydrazono-propionique, procédé pour leur préparation et médicaments les contenant
EP0046554A1 (fr) * 1980-08-23 1982-03-03 Roche Diagnostics GmbH Hydrazones N-substitués de l'acide pyruvique, procédés pour leur préparation et médicaments contenant ces composés
EP0048911A2 (fr) * 1980-09-26 1982-04-07 Roche Diagnostics GmbH Oximes o-substituées dérivées de l'acide alpha-cétocarboxylique, procédé de préparation et médicaments qui les contiennent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 92, Nr. 7, 18 February 1980, Columbus, Ohio, (US) T. TALSETH et al.: "Pharmacokinetics and Cardiovascular Effects in Rabbits of a Major Hydralazine Metabolite, the Hydralazine Pyruvic-Acid Dydrazone", see page 12, Abstract 51648z, J. Pharmacol. Exp. Ther. 1979, 211 (3), 509-13 *

Also Published As

Publication number Publication date
EP0298955A1 (fr) 1989-01-18
HUT41633A (en) 1987-05-28
DK79786A (da) 1986-02-20
AU572331B2 (en) 1988-05-05
IL75818A0 (en) 1985-11-29
AU4600285A (en) 1986-02-10
HU197668B (en) 1989-05-29
DK79786D0 (da) 1986-02-20
IL75818A (en) 1989-05-15

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