EP0298955A1 - UTILIZATION OF $g(a)-CETOCARBONIC ACID HYDRAZONES AND OXINES FOR TREATING CARDIAC OR CIRCULATORY DISEASES - Google Patents

Abstract

New medical use of hydrazones and alpha-ketocarbonic acid oximes of general formula (I) where Y represents an oxygen atom or an -NH- group; Z represents a saturated or unsaturated, straight-chain or branched alkyl group with up to 8 C atoms, optionally substituted one or more times by halogen or hydroxy; R1 represents a hydrogen, a nitrile, a formyl or an alkyl group comprising 1 to 8 C substituted, where appropriate one or more times, by a halogen, a hydroxy, a nitrile, a phenyl or a carboxyl. R2 represents a saturated or unsaturated, straight or branched chain alkyl group with up to 14 C atoms; an alkoxy group containing 1 to 6 C or an alkylthio group containing 1 to 6 C substituted optionally by a lower alkoxy, a cycloalkyl or an aryl; a cycloalkyl group having 3 to 8 C; a phenylamino; a phenyl-N-alkylamino; a phenyl mercapto; an aryl; or aryloxy; these last 5 substituents in the aryl part being able to be substituted one or more times if necessary by an alkyl comprising from 1 to 6 C, an alkoxy comprising from 1 to 6 C, a halogen, a trifluoromethyl, a hydroxy, an amino, an acetylamino, acetoxy, cyano, nitro or the methylenedioxy group. As well as their physiologically tolerable salts, esters and amides for the prophylaxis and/or treatment of heart and circulatory diseases, in particular ischemic heart diseases such as heart failure, angina pectoris or myocardial infarction.

Description

Use of α-ketocarboxylic acid hydrazones and oximes in cardiovascular diseases

The present invention relates to new uses of compounds which are known per se for other indications in medicine.

It is known that 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]).

However, 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.

According to DE-Al-27 26 210 and US 4,136,196, it was found that hydrazones of pyruvic acid, which contain phenelzine or similar compounds as the hydrazine component, show a considerably increased hypoglycemic effect compared to the corresponding hydrazines, while the MAO-inhibiting effect is practically complete is pushed back. EP-A1-1144 and US Pat. No. 4,206,231 describe that hydrazones of pyruvic acid with a hydrazine component deviating from phenelzine also have a considerably increased hypoglycemic effect compared to the corresponding hydrazines.

According to EP-Al-46554 and US 4,387,104, it was found that the introduction of a heteroatom in the radical X of the compounds of EP-A1-1144 leads to compounds which inhibit the absorption of glucose from the intestinal tract in a dosage range in which the blood sugar-lowering effect does not yet occur or only occurs insignificantly. The compounds are therefore suitable for the treatment of diseases in which strong and long-lasting hyperglycaemia occurs after the consumption of carbohydrate-containing foods. They are particularly suitable as therapeutic agents for the indications diabetes, prediabetes, obesity and atherosclerosis.

Finally, it was found in EP-A2-48 911 and US 4,425,360 that pyruvic acid oximes and their derivatives, which contain 0-alkylated hydroxylamines as the hydroxylamine component, have pharmacological properties which are not known from the hydroxylamines on which they are based. Compared to the pyruvic acid hydrazones known from DE-A1-27 26 210, EP-A1-1144 and EP-A1-46 554, the pyruvic acid oximes according to EP-A2-48 911 are distinguished by their high chemical stability in physiological media. They particularly inhibit intestinal glucose absorption. A pronounced hypoglycemic effect can also be observed. The compounds are therefore said to be outstandingly suitable for the treatment of diseases in which strong and long-lasting hyperglycaemia occurs after the consumption of carbohydrate-containing foods. It has now surprisingly been found that compounds of the general formula I

(I) in the

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,

and

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.

In addition to the known effects on glucose metabolism, they also have a positive effect on the functioning of the heart in hypoxic conditions

Further embodiments are given in claims 2-5 (general formulas II-V).

It is well documented that free fatty acids (FFA) are the preferred substrates for the mammalian heart that is adequately oxygenated. While the FFA is well tolerated by the heart muscle with sufficient oxygenation, physiological concentrations of these substrates can already have adverse effects under ischemic conditions. These manifest themselves above all through an increased enzyme release, a reduced rhythm threshold and a lowering of contractility.

If glucose is used exclusively as the substrate to be oxidized, an ATP / oxygen quotient of 3.17 is found; if only oleate is oxidized, this ratio is 2.82. This means that when switching from glucose to oleate oxidation, an approximately 13% increase in oxygen consumption could theoretically be expected. Corresponding investigations with the aid of isolated perfused hearts have shown, however, that the oxygen consumption after switching from glucose to FFA oxidation increases by more than 15%. This can only be interpreted in such a way that the oxygen-consuming effect of FFA in the heart muscle is not solely due to its oxidative metabolism, but must also be interpreted as the pharmacological property of these substrates themselves. A decoupling of the oxidative phosphorylation or an increased ATPase activity can be postulated as a possible explanation of this behavior.

Test protocol I

Perfusing isolated rats' hearts using an oxygenated Krebs-Henseleit solution with the addition of the substrates glucose (5mM) and lactate (1mM) and measuring the hemodynamic parameters as well as the oxygen requirement, shows that with the simultaneous supply of free fatty acids the oxygen uptake increases considerably, without changing the hemodynamic parameters such as cardiac output (cardiac output), stroke frequency and the maximum rate of pressure rise.

The fatty acid oxidation and the resulting increase in oxygen consumption can be eliminated by adding compounds of the general formula I.

This oxygen-saving effect can also be demonstrated on the hypoxic organ; for this purpose, the heart is perfused with a solution with reduced oxygen partial pressure under reduced flow over a period of about 30 minutes. This shows a significant reduction in cardiac output in the presence of palmitic acid. This hypoxia effect can be partially or completely eliminated by compounds of general form I. Table I:

Elimination of the hypoxia effect by 2- [E- (β-methylcinnamyl) hydrazono] propionic acid (compound A 25)

1 2 3

Control 0.5 mM palmitate 0.5 mM palmitate

+ 10 / uM (A 25) HZV 59.5 31.1 61.2

(% of the initial value

Such an effect has hitherto not been known for compounds of this type. The only known commercial product from which a comparable spectrum of activity is assumed is Intensain ^R (carbocromene).

It is known that 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.

These findings could be corroborated by studies with isolated liver mitochondria. As can be seen from the drawing, the free fatty acid to be transported is first activated with CoASH. Subsequently, the coupling to carnitine catalyzed by CAT I takes place on the outer mitochondrial membrane and then the carnitine portion on the inner mitochondrial membrane is cleaved off again by means of CAT II simultaneous activation of the fatty acid with CoASH. While all previously known synthetic and physiological (e.g. malonyl-CoA) inhibitors have an effect on CAT I, the compounds of the general formulas I - V have, in addition to the CAT I effect, also or predominantly an effect on CAT II. The test procedure and results can be found in the following test protocol II, palmitoyl-carnitine being used as the acyl component in the CAT measurement system. Therefore, the more precise term CPT is used instead of CAT.

Test protocol II

Carrying out the measurement of CPT (CAT) activity

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:

- sucrose (250 mM)

- triethanolamine HCl (10 mM)

- EDTA-K (1 mM)

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. To isolate the mitochondria, 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.

Determination of CPT activity

Test principle: CAT

Palmitoyl-Carnitine (C ¹⁴ ) + CoASH → Palmitoyl-CoA + Carnitine (C ¹⁴ )

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.

If, on the other hand, 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):

KCl 120 mM

KH ₂ PO ₄ 5 mM

TRA x HCl 20 mM

EDTA K ₂ x 2H ₂ O 0.5 mM

L-malate 0.5 mM

Sucrose 25 mM

MgCl ₂ x 6H ₂ O 5 mM

Bovine albumin 5 mg / ml

The following substrates and substances were used (final concentration in the test):

CoA 0.10 mM

Palmitoyl-carnitine (C ¹⁴ ) 0.10 mM

Test substances 0.01 mM

(BM 42,304 and phenformin 0.05 mM

Test approach for the determination of CPT II and CPT I activity (in ml):

Ink. H ₂ O CoASH SubMitoPalm. HClO ₄

Med. Punch chondr. Carn. 70%

Blank value 0.5 0.5 - - - - -

100% value 0.5 0.5 - - - 0.1 -

CPT II

O value 0.5 0.3 - - 0.1 0.1 0.1

Controls 0.5 0.3 - - 0.1 0.1 0.1

Substance 0.5 0.2 - 0.1 0.1 0.1 0.1

Substance 0.5 0.2 - 0.1 0.1 0.1 0.1

CPT I

O value 0.5 0.2 0.1 - 0.1 0.1 0.1

Controls 0.5 0.2 0.1 - 0.1 0.1 0.1

Substance 0.5 0.1 0.1 0.1 0.1 0.1 0.1

Substance 0.5 0.1 0.1 0.1 0.1 0.1 0.1

0.5 ml incubation medium and the corresponding amount of water, coenzyme A, the respective substance and the mitochondrial suspension were pipetted into 10 ml Erlenmeyer flasks in accordance with the pipetting scheme described above. All samples, with the exception of those of the zero value, were then incubated in the shaking water bath at 37 ° C. and 100 RPM without being sealed for 10-30 minutes. The zero control was immediately stopped with 0.1 ml -70% HClO ₄ . Then 0.1 ml was added to all samples with the exception of the blank value

Pipette palmitoyl-carnitine (C ¹⁴ ) every 5 sec. After 5 minutes of incubation in a water bath at 37 ° C. and 100 RPM, 0.1 ml of 70% HClO ₄ were added at the same time interval to stop the reaction.

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.

Calculating CAT activity ::

^C PC =

Turnover =

^C PC ... concentration of the palmitoyl-carnitine used [nmol / ml]

DPM ... [decays / min]

^C Prot. .. concentration of the mitochondrial protein used [mg]

Spec. Act. Spec. Activity of the palmitoyl-carnitine used [KBq / mg

T ... incubation time [min]

Turnover ... Carnitine formed (C ¹⁴ ) [nmol / min / mg / protein]

The results are summarized in the following table: Table II:

Effect of compounds of general formula I on CPT I and CPT II on isolated guinea pig liver mitochondria

* see. Pages 24 29

The compounds of the general formulas I to V are therefore suitable for the treatment of cardiovascular diseases. In particular, however, for such diseases that are associated with an undersupply of oxygen (ischemia) of the heart, such as in particular heart failure, angina pectoris and heart attack.

The provision of a further class of compounds (the known compounds of the general formulas I - V) for the new indications thus represents an enrichment for the pharmaceutical industry.

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 (general formulas I and III) 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.

In all cases, unbranched alkylene chains A are preferably understood to mean the following:

- (CH ₂ ) _χ -with X = 1 - 8, -CH = CH-CH ₂ - and -C≡C-CH ₂ -.

The following are particularly preferred as branched groups A:

and

For the purposes of the invention, 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, α- 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:

A 1) 2- (phenethylhydrazono) propionic acid A 2) 2- (4-methoxyphenethylhydrazono) propionic acid A 3) 2- (4-chlorophenethylhydrazono) propionic acid A 4) 2- [2- (p-tolyl) ethylhydrazono] -propionic acid A 5) 2- (p-hydroxyphenethylhydrazono) -propionic acid A 6) 2- (2-methylphenethylhydrazono) -propionic acid A 7) 2- (4-fluorophenethylhydrazono) -propionic acid A 8) 2- (3-trifluoromethyl-phenethylhydrazono) -propionic acid A 9) 2- (phenethylhydrazono) -propionic acid ethyl ester A 10) 2- (phenethylhydrazono) -propionic acid methyl ester A 11) 2- (phenethylhydrazono) -propionamide A 12) sodium 2- (3-phenylpropylhydrazono) propionate A 13) sodium 2- (cinnamylhydrazono) propionate A 14) sodium 2- (2-methoxyphenethylhydrazono) propionate A 15) sodium 2- (ß-methylcinnymylhydrazono) propionate A 16) sodium 2- (2-phenylpropylhydrazono) propionate A 17 ) Sodium 2- (3-bromophenethylhydrazono) propionate A 18) Sodium 2- (3,4-methylenedioxyphenethylhydrazono) propionate A 19) 2- (phenethylhydrazono) propionic acid A 20) 2 - [(3-methylcinnarayl ) hy drazono] propionic acid A21) 2 - [(2-chloroaminamyl) hydrazono] propionic acid A 22) 2 - [(3-chlorocinnamyl) hydrazono] propionic acid A 23) 2 - [(4-chlorocinnamyl) hydrazono] propionic acid A 24 ) 2- [Z- (β-Methylcinnamyl) hydrazono] propionic acid A 25) 2- [E- (β-Methylcinnamyl) hydrazono] propionic acid A 26) 2- [2- (m-tolyl) ethylhydrazono] propionic acid A 27) 2- (3-methoxyphenethylhydrazono) propionic acid A 28) 2- (2-chlorophenethylhydrazono) propionic acid A 29) 2- (4-phenylbutylhydrazono) propionic acid A 30) 2- (5-chloro-2-methoxy- phenethylhydrazono) propionic acid A 31) 2- (4-phenyl-2-butenylhydrazono) propionic acid A 32) 2- (4-phenyl-3-butenylhydrazono) propionic acid A 33) 2- (3-phenyl-butylhydrazono) propionic acid A 34) 2- (3-phenyl-2-butenylhydrazono) propionic acid B 35) 2- (2-methyl-3-phenyl-propyl-hydrazono) propionic acid B 1) 2- (2-cyclohexyl-ethylhydrazono) propionic acid B 2) 2- (isobutylhydrazono) propionic acid B 3) 2- ( Methylallylhydrazono) propionic acid B 4) 2- (propylhydrazono) propionic acid B 5) 2- (isopentylhydrazono) propionic acid B 6) 2- (octylhydrazono) propionic acid B 7) 2- (cyclohexylmethyl hydrazono) propionic acid B 8) 2 - (Isopropylhydrazono) propionic acid B 9) 2- (allylhydrazono) propionic acid B 10) 2- (butylhydrazono) propionic acid B 11) 2- (sec-butylhydrazono) propionic acid B 12) 2- (tert-butylhydrazono) propionic acid B 13) 2- (hexylhydrazono) propionic acid B 14) 2- (4-methylpentylhydrazono) propionic acid B 15) 2- (2-ethylbutylhydrazono) propionic acid B 16) 2- (5-hexenylhydrazono) propionic acid B 17 ) 2- (Heptylhydrazono) propionic acid B 18) 2- (Cyclopentylhydrazono) propionic acid B 19) 2- (2-Cyclopentylethylhydrazono) propionic acid B 20) 2- [2- (3-Cyclohexen-l-yl) ethylhydrazono] -propionic acid B 21) 2- (2-cycloheptylethylhydrazono) -propionic acid B 22 ) 2-Decylhydrazono) propionic acid B 23) 2- (nonylhydrazono) propionic acid B 24) 2- (3-cyclohexylpropylhydrazono) propionic acid B 25) sodium 2- (pentylhydrazono) propionate B 26) sodium 2- (2 -cyclohexyl-ethylhydrazono) -propionate B 27) sodium 2- (3-cyclohexyl-propyl-hydrazono) -propionate B 28) 2- (9-decenylhydrazono) -propionic acid B 29) 2- (2-hexenylhydrazono) -propionic acid B 30) 2- (Methylhydrazono) propionic acid B 31) 2- (5-Methylhexylhydrazono) propionic acid B 32) 2- (Decylhydrazono) propionic acid amide B 33) 2- (Heptylhydrazono) propionic acid methyl ester B 34) 2- (nonylhydrazono) propionic acid methyl ester B 35) 2- (4-Hexenylhydrazono) propionic acid B36) 2- (octadecylhydrazono) propionic acid B37) 2- (3-butenylhydrazono) propionic acid B38) 2- (3,3-dimethylbutylhydrazono) propionic acid B39) 2- (3-methyl-octylhydrazono) propionic acid B40) 2- (3-Cyclohexyl-2-propenylhydrazono) propionic acid B41) 2- (dodecylhydrazono) propionic acid B42) 2- (4-methylhexylhydrazono) propionic acid B43) 2- (1-methylhexylhydrazono) propionic acid B44) 2- (2-ethylhexylhydrazono -propionic acid B45) 2- (3-hexenylhydrazono) -propionic acid B46) 2- (3-cyclopentyl-propylhydrazono) -propionic acid B47) sodium 2- (3-cyclohexyl-2-methyl-2-propenylhydrazono) - propionate B48) 2 - (Butinylhydrazono) propionic acid B49) 2- (3,5-dimethylhexylhydrazono) propionic acid B50) 2- (3,7-dimethyl-6-octenylhydrazono) propionic acid B51) 2- / 2- (1-cyclohexen-l-yl ) -ethylhydrazono / -propionic acid B52) 2- (3-cyclohexyl-2-methyl-2-propenylhydrazono) - propionic acid B53) 2- [2- (2-cyclohexen-1-yl) -ethylhydrazono] -propionic acid B54) 2- (2 -Propinylhydrazono) propionic acid B55) 2- (2-hexinylhydrazono) propionic acid B56) 2 - (3-pentenylhydrazono) propionic acid B57) 2- [3- (3-cyclohexen-l-yl) -2-methyl-2-propenylhydrazono] propionic acid

C 1) 2- (2-p-tolyloxyethylhydrazono) propionic acid C 2) 2- [2- (2-ethoxyethoxy) ethylhydrazono] propionic acid C 3) 2- (2-phenoxyethylhydrazono) propionic acid C 4) 2- (3-phenoxypropylhydrazono) propionic acid C 5) sodium 2- (2-phenoxypropylhydrazono) propionate C 6) sodium 2- [2- (2-methoxyethoxy) ethylhydrazono] propionate C 7) sodium 2- (2-benzyloxyethylhydrazono) propionate C 8) sodium 2 - (2-allylthioethylhydrazono) propionate C 9) sodium 2- (2-phenylthioethylhydrazono) propionate C 10) 2- (2-allyloxyethylhydrazono) propionic acid C 11) 2- (6-methoxyhexylhydrazono) propionic acid C 12) 2- (5-Ethoχypentylhydrazono) propionic acid

C 13) 2- (4-Propoxybutylhydrazono) propionic acid

C 14) 2- [2- (2-Cyclohexylethoxy) ethylhydrazcmo] propionic acid

C 15) 2- (3-Benzyloxypropylhydrazono) propionic acid

C 16) 2- [2- (2-Methoxyethylthio) ethylhydrazono] propionic acid

C 17) 2- [2- (β-Methylcinnamyloxy) ethylhydrazono] propionic acid

D 1) Sodium 2- (2-methallyloxyimino) propionate D 2) Sodium 2- (2-methoxyethyloxyimino) propionate D 3) Sodium 2- (3-phenylpropyloxyimino) propionate D 4) Sodium 2- (2-phenoxyethyloxyimino ) propionate D 5) sodium 2- (2-cyclohexylethyloxyimino) propionate D 6) 2- (2-p-tolylethyloxyimino) propionic acid D 7) 2- (2-phenylethyloxyimino) propionic acid D 8) 2-hexyloxyiminopropionic acid D 9) 2- Octyloxyiminopropionic acid D 10) 2- (3-phenyl-2-propynyloxyimino) propionic acid D 11) 2- (y-methylcinnamyloxyimino) propionic acid D 12) 2-cinnamyloxyiminopropionic acid D 13) 2- (ß-methylcinnamyloxyimino) propionic acid D 14) 2- ( 3-chlorocinnamyloxyimino) propionic acid D 15) 2- (2-chlorocinnamyloxyimino) propionic acid D 16) 2- (4-chlorocinnamyloxyimino) propionic acid D 17) 2- (allyloxyimino) propionic acid D 18) 2- (4-fluorocinnamyloxyimino) propionic acid D 19) 2- (3-trifluoromethylcinnamyloxyimino) propionic acid D 20) 2- (3-methylcinnamyloxyimino) propionic acid D 21) 2- (4-tert-butylcinnamyloxyimino) propionic acid D 22) 2- (3-methoxycinnamyloxy imino) propionic acid D 23) 2- (2-methoxycinnamyloxyimino) propionic acid D 24) 2- (5-chloro-2-methylcinnamyloxyimino) propionic acid D 25) 2- (5-chloro-2-methoxycinnamyloxyimino) propionic acid D 26) 2- [ 3- (1-Naphthyl) -2-propenyloxyimino] propionic acid D 27) 2- (3.5-dichlorocinnamyloxyimino) propionic acid D 28) 2- (5-chloro-2-methoxy-ß-methylcinnamyloxyimino) propionic acid D 29) 2- (5 -Brom-2-methoxycinnamyloxyimino) propionic acid D 30) 2- (5-fluoro-2-methoxycinnamyloxyimino) propionic acid

D 31) 2- (2-methoxy-5-trifluoromethylcinnamyloxyimino) propionic acid

D 32) 2- (2,5-Dimethoxycinnamyloxyimino) propionic acid

D 33) 2- (2-methoxy-5-methylcinnamyloxyimino) propionic acid

D 34) 2- (Cinnamyloxyimino) propionic acid ethyl ester

D 35) 2- (Cinnamyloxyimino) propionic acid amide

D 36) 2- (Cinnamyloxyimino) propionic acid N- (2-hydroxyethylamide)

D 37) 4- [2- (cinnamyloxyimino) propionyl] -1-methylpiperazine

D 38) 3- [2- (Cinnamyloxyimino) propionylamido] propionic acid ethyl ester

D 39) 2- (Cinnamyloxyimino) -3-fluoropropionic acid

D 40) 3-chloro-2-cinnamyloxyimino-propionic acid

D 41) Cinnamyloxyiminoacetic acid

D 42) 2-cinnamyloxyiminobutyric acid

D 43) 2-cinnamyloxyimino-3-methylbutyric acid

D 44) 2-cinnamyloxyimino-valeric acid

D 45) 2-cinnamyloxyimino-4-methylvaleric acid

D 46) 2-cinnamyloxyimino-3-methylvaleric acid

D 47) 2-cinnamyloxyimino-octanoic acid

D 48) 2-cinnamyloxyimino-3-phenylpropionic acid

D 49) 2- (Cinnamyloxyimino succinic acid

D 50) 2-cinnamyloxyimino-glutaric acid

D 51) Sodium 2- (4-phenylbutoxyimino) propionate

D 52) Sodium 2- (5-phenylpentoxyimino) propionate

D 53) Sodium 2- (2-phenoxypropoxyimino) propionate

D 54) 2- (3-Phenoxyρropoxyimino) propionic acid

D 55) 2- [2- (4-chlorophenoxy) propoxyimino] propionic acid

D 57) 2-cinnamyloxyimino-propionic acid

D 58) 2-Cinnamyloxyiminopropionic acid methyl ester

D 59) 2- (3-fluorocinnamyloxyimino) pyruvic acid

D 60) 2- [3- (3-methylphenyl) propoxyimino] propionic acid

D 661) 2- [3- (4-methylphenyl) propoxyimino] propionic acid

D 62) 2- [3- (3-chlorophenyl) propoxyimino] propionic acid

D 63) 2- [3- (4-chlorophenyl) propoxyimino] propionic acid

D 64) 2- [3- (3-methoxyphenyl) propoxyimino] propionic acid D 65) 2- [3- (4-methoxyphenyl) propoxyimino propionic acid

D 66) 2- (2-methyl-3-phenylpropoxyimino) ρropionic acid

D 67) 2- [5- (3-chlorophenyl) pentyloxyiminopropionic acid

D 68) 2- [5- (4-chlorophenyl) pentyloxyimino] propionic acid

D 69) 2- [5- (4-methoxyphenyl) pentyloxyimino] propionic acid

D 70) 2- (3-cyclohexyl-2-propenyloxyimino) propionic acid

D 71) 2- (4-methylcinnamyloxyimino) propionic acid

D 72) 2- (3-t-butylcinnamyloxyimino) propionic acid

D 73) 2- (3-bromocinnamyloxyimino) propionic acid

D 74) 2- (3-cyanocynamyloxyimino) propionic acid

D 75) 2- (3.4-methylenedioxycinnamyloxyimino) propionic acid

D 76) 2- (3-nitrocinnamyloxyimino) propionic acid

D 77) 2- (3-aminocinnamyloxyimino) ρropionic acid

D 78) 2- (3-acetamidocinnamyloxyiraino) propionic acid

D 79) 2- [3- (3-methylphenyl) -2-propynyloxyimino] propionic acid

D 80) 2- [3- (4-methylphenyl) -2-propynyloxyimino] propionic acid

D 81) 2- [3- (3-chlorophenyl) -2-propynyloxyimino] propionic acid

D 82) 2- [3- (4-chlorophenyl) -2-propynyloxyimino] propionic acid

D 83) 2- [3- (4-methoxyphenyl) -2-propynyloxyimino] propionic acid

D 84) 2- (3-hydroxy-3-phenylpropoxyimino) propionic acid

D 85) 2- (2-hydroxy-3-phenylpropoxyimino) propionic acid

D 86) 2- (2-chloro-3-phenylpropoxyimino) propionic acid

D 87) 2- (β-chlorocinnamyloxyimino) propionic acid

D 88) 2- (3-oxo-3-phenylpropoxyimino) propionic acid

D 89) 2- (2-oxo-3-phenylpropoxyimino) propionic acid

D 90) 2- [2- (3-chlorophenoxy) propoxyimino] propionic acid

D 91) 2- [2- (4-Methoχγphenoxy) propoxyimino] propionic acid

D 92) 2- [3- (3-chlorophenoxy) propoxyimino] propionic acid

D 93) 2- [3- (4-chlorophenoxy) propoxyimino] propionic acid

D 94) 2- [3- (4-methoxyphenoxy) propoxyimino] propionic acid

D 95) 2- (2-hydroxy-3-phenoxypropoxyimino) propionic acid

D 96) 2- (3-anilino-propoxyimino) propionic acid

D 97) 2- [3- (N-methylanilino) propoxyimino] propionic acid

D 98) 2- (3-anilino-2-hydroxypropoxyimino) propionic acid

D 99) 2- (3-phenylthiopropoxyimino) propionic acid D 100) 2- (2-cinnamyloxyethoxyimino) propionic acid D 101) 3-fluoro-2- (2-propenyloxyimino) propionic acid D 102) 2- (2-propenyloxyimino) butyric acid D 103) 3-fluoro-2-hexyloxyiminopropionic acid D 104) 2- (2-hexyloxyimino) butyric acid D 105) 3-hydroxy-2- (3-phenylpropoxyimino) propionic acid D 106) 3-fluoro-2- (3-phenylpropoxyimino) propionic acid D 107) 2- (3-phenylpropoxyimino) butyric acid D 108) 2- [3- (3-chlorophenyl) propoxyimino] -3-fluoropropionic acid D 109) 2- [3- (3-chlorophenyl) propoxyimino] butyric acid D 110) 3-fluoro-2- [3- (3-methylphenyl ) propoxyimino] propionic acid D 111) 2- [3- (3-methylphenyl) propoxyimino] butyric acid D 112) 3-oxo-2-cinnamyloxyimino-propionic acid D 113) 2-cinnamyloxyimino-3.3-dichloropropionic acid D 114) 2-cinnamyloxyimino -3-cyano-propionic acid D 115) 2-cinnamyloxyimino-4-cyano-butyric acid D 116) 2-cinnamyloxyimino-3-hydroxy-propionic acid D 117) 2- (3-chlorocinnamyloxyimino) 3-fluoropropionic acid D 118) 2- (3rd -Chlorcinnamyloxyimino) butyric acid D 119) 3-fluoro-2- (3-methylcinnamyloxyimino) prop ionic acid D 120) 2- (3-methylcinnamyloxyimino) butyric acid D 121) 3-hydroxy-2- (3-phenylpropin-2-yloxyimino) propionic acid D 122) 3-fluoro-2- (3-phenylpropin-2-yloxyimino) propionic acid D 123) 2- (3-phenylpropin-2-yloxyimino) butyric acid D 124) 2- [3- (3-chlorophenyl) propin-2 - yloxyimino) 3-fluoropropionic acid D 125) 2- [3- (3-chlorophenyl) propyne 2-yloxyimino] butyric acid D 126) 3-fluoro-2- [3- (3-methylphenyl) propin-2-yloxyimino] propionic acid D 127) 2- [3- (3-methylphenyl) propin-2-yloxyimino] butyric acid D 128) 3-fluoro-2- (2-phenoxypropoxyimino) propionic acid D 129) 2- (2-phenoxypropoxyimino) butyric acid D 130) 2- (3,5-di-tert-butyl-4-hydroxycinnamyloxyimino) propionic acid D 131) 2- (2 -n-propoxycinnamyloxyimino) propionic acid D 132) 2- (5-chloro-3-methylcinnamyloxyimino) propionic acid D 133) 2- [3- (3-trifluoromethylphenyl) propoxyimino] propionic acid D 134) 2- (4-methoxycinnamyloxyimino) propionic acid D 135) 2- (3- Phenylpropoxyimino) octanoic acid D 136) 2- [3- (3-chlorophenyl) propoxyimino] pentanoic acid D 137) 2- [3- (3-chlorophenyl) propoxyimino] octanoic acid D 138) 2- [5- (3-chlorophenyl) pentyloxyimino] butyric acid D 139) 2- [3- (3-methoxyphenyl) propoxyimino] butyric acid D 140) 2- [3- (3-trifluoromethylphenyl) propoxyimino] butyric acid D 141) 2- (3-methylcinnamyloxyimino) butyric acid D 142) 2- ( 3-trifluoromethylcinnamyloxyimino) butyric acid

and the associated free acids or physiologically acceptable salts, esters and amides.

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.

To produce drugs, the active ingredient is mixed with solid or liquid carriers and then brought into the desired shape. 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). For the oral

If desired, suitable preparations can be applied 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. Such additives are e.g. B. acetate or tartrate buffer, ethanol, complexing agent (such

Ethylenediamine-tetraacetic acid and its non-toxic salts) or high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation.

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.

Claims

Pat claims

1 . Use of α-ketocarboxylic acid hydrazones and oximes of the general formula I

(I) in the

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 one or more times by Halogen, hydroxy, nitrile, phenyl or carboxyl is substituted, means nitrile or formyl,

and

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, where 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, and their physiologically tolerable salts, esters and amides for combating cardiovascular diseases.

2. Use of 2- (phenylalkylhydrazono) propionic acid derivatives of the general formula II

(II)

in the

R ₃ and R _{4 are the} same or different and are hydrogen, halogen, trifluoromethyl, alkyl, hydroxyl, acyloxy, alkoxy or together the methylenedioxy group and X is a straight-chain, saturated or unsaturated alkylene group with 2-4 C atoms, which are optionally in the β or position to the nitrogen is substituted by an alkyl group,

as well as their physiologically compatible salts, esters and amides for combating cardiovascular diseases.

3. Use of 2- (hydrazone propionic acid derivatives of the general formula III

( _III)

in the

R is a straight-chain, branched or cyclic, saturated or unsaturated alkyl radical and

X is a valence line or a straight-chain or branched, saturated or unsaturated alkylene group with 1-4

Is carbon atoms and their physiologically tolerable salts, esters and amides for combating cardiovascular diseases.

4. Use of pyruvic acid hydrazones of the general formula IV

in the

R 'is an aryl radical or a straight-chain or branched, saturated or unsaturated alkyl radical which can be substituted by a lower alkoxy, a cycloalkyl or an optionally substituted aryl radical and

X represents the group -A-B-, with the proviso that A is attached to the nitrogen atom and B to the radical R,

wöbe i

A represents a straight-chain or branched alkylene group having 2-8 carbon atoms, with a straight-chain section of at least 2 carbon atoms, which connects B to the nitrogen atom, and

B represents an oxygen or a sulfur atom and their physiologically tolerable salts, esters and amides for combating cardiovascular diseases.

5. Use of pyruvic acid oximes of the general formula V

/ ^R 1 R "- A - 0 - N = C ^ (V)

XOOH

in the

R "is hydrogen, a C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkoxy, cinnamyloxy, phenylamino, phenyl-N-alkylamino, phenylmercapto, an aryl or aryloxy group, the aryl, Radical one or more times by C _1-6 alkyl, C _1-6 alkoxy, halogen, hydroxy,

Trifluoromethyl, amino, acetylamino, nitrile, nitro or a methylenedioxo group can be substituted,

A is a straight-chain or branched, saturated or unsaturated alkylene chain with up to 10 C atoms, which is optionally substituted one or more times by halogen or hydroxy,

and

R _{1 is} hydrogen, a C ₁ -C ₈ alkyl group which is optionally mono- or polysubstituted by halogen, hydroxy, nitrile, phenyl or carboxyl, nitrile or formyl, and their physiologically tolerable salts, esters and amides for combating cardiac and circulatory diseases.

Use of compounds of general formulas I, II, III, IV or V according to any one of claims 1-5 for the preparation of agents for cardiovascular diseases.

7. Use according to any one of claims 1-6, characterized in that the cardiovascular disease is a (ischemic) disease caused by a pathological undersupply of the heart.

8. Use according to claim 7, characterized in that the disease is heart failure, angina or heart attack.

9. Use according to any one of claims 1-8, characterized in that the compound is selected from the group

A 13) Sodium 2- (cinnamylhydrazono) propionate C 3) 2- (2-phenoxyethylhydrazono) propionic acid C 6) sodium 2- [2- (2-methoxyethoxy) ethylhydrazono] propionate

B 4) 2- (Propylhydrazono) propionic acid

A 15) Sodium 2- (β-methylcinnymylhydrazono) propionate A 14) Sodium 2- (2-methoxyphenethylhydrazono) propionate

A 17) sodium 2- (3-bromophenethylhydrazono) propionate D 6) 2- (2-p-tolylethyloxyimino) propionic acid D 16) 2- (4-chlorocinnamyloxyimino) propionic acid

D 15) 2- (2-chlorocinnamyloxyimino) propionic acid

D 14) 2- (3-chloroaminyloxyimino) propionic acid

D 20) 2- (3-methylcinnamyloxyimino) propionic acid

D 19) 2- (3-trifluoromethylcinnamyloxyimino) propionic acid

D 12) 2-cinnamyloxyiminopropionic acid

D 59) 2- (3-fluorocinnamyloxyimino) pyruvic acid

D 73) 2- (3-bromocinnamyloxyimino) propionic acid

D 107) 2- (3-phenylpropoxyimino) butyric acid

D 142) 2- (3-trifluoromethylcinnamyloximino) butyric acid

D 134) 2- (4-methoxycinnamyloximino) propionic acid

A 22) 2 - [(3-chlorocinnamyl) hydrazono] propionic acid

A 20) 2 - [(3-methylcinnamyl) hydrazono] propionic acid

10. Cardiovascular drug containing a compound of general formula I, II, III, IV or V according to any one of claims 1-5 or a physiologically acceptable salt, ester or amide thereof.

11. Orally administrable cardiovascular drug according to claim 10

12. Ready-to-sell pack with at least one substance of the general formula I, II, III, IV or V according to one of claims 1-5 as a pharmaceutical active ingredient and instructions for its use as cardiovascular agents.