HU197668B - Process for producing pharmaceutical compositions comprising alpha-ketocarboxylic acid hydrazines and oximes - Google Patents

Abstract

New medical utilization of alpha -cetocarbonic acid hydrazones and oxines having the general formula (I) wherein I represents an oxygen atom or a group-NH-; Z is a saturated or unsaturated straight or branched chain alkyl group having up to 8 atoms of carbon, optionally substituted once or a plurality of times by a halogen or a hydroxy; R1 is hydrogen, nitrile, formyl or an alkyl group comprising from 1 to 8 C optionally substituted once or a plurality of times by halogen, hydroxy, nitrile, phenyl or carboxyl; R2 represents a saturated or unsaturated straight or branched chain alkyl group with up to 14 atoms of carbon; an alkoxy group comprising from 1 to 6 C or alkylthio having from 1 to 6 C substituted optionally by a lower alkoxy, a cycloalkyl or an aryl; a cycloalkyl group comprising from 3 to 8 C; a phenyl amino; phenyl-N-alkylamino; phenylmercapto; aryl; or aryloxy; these last five substituents being optionally substituted in the aryl part once or a plurality of times by an alkyl comprising from 1 to 6 C, an alkoxy having from 1 to 6 C, a halogen, trifluoromethyl, hydroxy, amino, acetylamino, acetoxy, cyano, nitro or the methylendioxy group; as well as the salts, esters and amides thereof which are physiologically acceptable for the prophylaxis and/or treatment of cardiac and circulatory diseases, particularly ischemic cardiac diseases such as cardiac insufficiency, angina pectoris or myocardial infarction.

Description

FIELD OF THE INVENTION The present invention relates to the preparation of medicaments for the new use of known compounds in medicine for other indications.

It is known that some monoamine oxidase inhibitors, e.g. high doses of phenelcin (2-phenylethylhydrazine) or mebazine (1-phenylethylhydrazine) may be hypoglycemic [Adnitt, Ρ. 1: Hypoglycemic Action of Mono Amino Oxidase Inhibitors, Diabetes 17: 628-633 (1968), Wickstrom, Petterson, K-: Treatment of Diabetes with Mono Amino Oxidase Inhibitors, Chain 2: 995-97 (1964), Cooper, AJ. Reddie, KMG: Hypotensive Collapse and Hypoglycemia After Mebazine - A Mono Amine Oxidase Inhibitor, Chain 1: 1133-1135 (1964)].

However, the main effect is the monoamine oxidase (MAO) inhibitory effect, which is why these compounds can be used in medicine for the treatment of psychiatric disorders Jván Praag, HM, Leijnse, B .: The influence of somatic antidepressant drugs on glucose metabolism in depressed patients, Clin. Chim. Acta 8: 466-475 (1963)] but are not useful as antihypertensive drugs.

DE-A1-2726210 and U.S. Pat. U. S. Patent Nos. 5,102 to 6,102 to 6,102 disclose that hydrazones of pyruvic acid, which contain phenelcin or other similar compounds as the hydrazine component, exhibit significantly stronger hypoglycemic activity against the corresponding hydrazines, while the monoamine oxidase inhibitory activity is substantially

EP-A1-1144 and U.S. Pat. U. S. Patent Nos. 5,109,125 to 5,102,115 disclose that pyrosuccinic hydrazines containing a hydrazine component other than phenelcin have a significantly stronger hypoglycemic effect than the corresponding hydrazines.

EP-A1-46554 and US-A-4,387,104. EP-A1-1144 discloses that U.S. Pat. The introduction of a heteroatom into Group X of the compounds of this patent discloses compounds which inhibit the absorption of glucose from the digestive tract in a dosage range in which the antihypertensive activity is absent or negligible. Therefore, these compounds are useful in the treatment of diseases in which severe and prolonged hyperglycemia occurs after ingestion of a hydrocarbon-containing diet. They are mainly suitable for the treatment of diabetes, prediabetes, adipositis and atherosclerosis.

Finally, EP-A2-48911 and U.S. Pat. U.S. Patent Nos. 4,179,125 to 6,102,125 disclose that pyrimidic acid oximes and their derivatives containing O-alkylated hydroxylamines as a hydroxylamine component have medicinal properties not known for the underlying hydroxylamines. DE-AL-2726210, EP-A1-1144 and EP-A1-46554. EP-A2-48911 with respect to the pyruvic acid hydrazones known from the patents. The pyrosuccinic acid oximes known from U.S. Patent No. 5,102,125 are distinguished by their high chemical stability in physiological media. In particular, they inhibit glucose resorption in the digestive tract. In addition, a pronounced hypoglycemic effect is observed. Therefore, the compounds are well suited for the treatment of diseases in which severe and prolonged hyperglycemia occurs after ingestion of a hydrocarbon-containing diet.

Surprisingly, it has been found that the formula (1) compounds of the formula, Me ₁₅ monographs

Y is -NH,

Z is a linear or branched saturated C 1 -C 4 alkylene group,

R, C 1-4 alkyl,

R _{2 is} a linear or branched, unsaturated C 1 -C 4 alkoxy substituted with unsaturated C 1 -C 4 alkoxy, and their physiologically tolerable salts, in addition to their effects on known glucose metabolism, have a positive effect on cardiac function in hypoxic conditions.

They are similar in activity to compounds (II), (III), (IV) and (V) related to the compounds of formula (1).

Compounds of formula 3q and their physiologically tolerable salts.

In the formula 2-phenylalkylhydrazono-propionic acid derivatives of formula II, R ₃ is halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, and

X is a linear, saturated or unsaturated C 2 -C 4 alkylene group which is optionally substituted with a C 1 -C 4 alkyl group in the β-or gamma position of the nitrogen atom. 2-Hydrazonopropionic acid derivatives of the general formula (III)

R is a linear or branched C 1 -C 5 alkyl group and

X represents a valence bond.

In the formula of pyrosuccinic acid hydrazones of formula IV

R 'is phenyl or naphthyl,

5Q X is a group of formula A-B, wherein A is attached to the nitrogen atom and B is to the R 'substituent and

A is a straight chain alkylene group having 2 to 4 carbon atoms and

B is oxygen.

The carboxylic acid oxime derivatives represented by the general formula (V)

R 'is phenyl or naphthyl which

They may be singly substituted with C 1-4 alkyl, C 1-4 alkoxy, halogen, θθ or trifluoromethyl,

A is straight or branched, saturated or unsaturated, up to 5 carbon atoms tar ⁺ Almazan alkylene chain, and

R, C 1-4 alkyl,

-3197668; and pharmaceutically acceptable salts thereof.

Free fatty acids (FFAs) are known to be preferred substrates for the oxygenated mammalian heart. While free oxygenation of the cardiac muscle is well tolerated with adequate oxygenation, even under physiological concentrations of these substrates, adverse effects may occur under ischemic conditions. These are primarily manifested in enhanced enzyme release, decreased arrhythmic waves, and decreased cytotoxicity.

When used as the substrate to be exclusively oxidized to glucose, the ATP / oxygen ratio is 3.17, while for the oxidation of oleate it is 2.82.

This means that when switching from glucose to oleate oxidation, the use of oxygen would theoretically be expected to increase by about 13%. However, appropriate experiments with isolated perfused hearts have shown that oxygen utilization increases by more than 15% when switching from glucose oxidation to FFA oxidation.

This can only be explained by the fact that the oxygen consuming effect of free fatty acids in myocardium is not only dependent on their oxidative metabolism, but that these substrates must also have medicinal properties. A possible explanation for this behavior is the switching off of oxidative phosphorylation or an increase in ATPase activity.

I. Examination

When perfused rat heart hearts using Krebs-Henseleit solution with addition of glucose (5 mM) and lactate (1 mM) substrates and measurement of hemodynamic parameters as well as oxygen demand, the oxygen uptake during simultaneous delivery of free fatty acids is increases without altering hemodynamic parameters such as suction volume (HZV), pulse rate and maximum pressure rise rate.

The increase in fatty acid oxidation and the resulting oxygen uptake can be increased by the addition of compounds of formula (1).

This oxygen-saving effect can also be detected on hypoxic organs; to do this, the heart is perfused for about 30 minutes with a slower flow solution in which the partial pressure of oxygen is reduced. In this experiment, in the presence of palmitic acid, there is a marked decrease in heart rate (HZV). This hypoxic effect can be fully or partially enhanced by the compounds of formula (I).

Table I

Increased hypoxic activity with 2- (TZ-, beta-methylcinnamyl) -hydrazono-propionic acid (A 25). compound /

1 2 3 control 0.5 mM palmitate 0.5 mM palmitate + 10 µM / A 25 /

HZV 59.5 /% of baseline /

31.1 61.2

Such an effect has not yet been known for this type of compound. The only commercial product that has a comparative spectrum is Intensain (Carbocromen).

It is known that the short- and long-chain free fatty acids metabolically essentially differ in that the hosszú4 chain fatty acids into the mitochondria membrane penetrate carnitine acyl transferase-system assistance ⁶⁰ vei through (see attached figure), while the short chain fatty acids of mitochondrial is achieved without the aid of this reaction chain. Therefore, it is likely that the compounds of formulas I to V exert their action through inhibition of CAT.

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These facts can be confirmed by a separate liver mitochondrial examination. As shown in the figure, the free fatty acids to be transported are first activated by CoASH. This is followed by CAT I-catalyzed coupling to the carnitine on the outer mitochondrial membrane, followed by CAT II catalyzed cleavage on the inner mitochondrial membrane of the carnitine moiety by simultaneous activation of the fatty acid with CoASH. While all known synthetic and physiological (eg malonyl-CoA) inhibitory agents exert their effects on CAT I, the compounds of formula (I) - (V) predominantly act on CAT II in addition to the CAT I effect. too. Execution of the experiment and the results are shown in the following Section II. experiment, which used palmitoyl carnitine as the acyl component in the CAT measurement system. Therefore, we use the more accurate concept of CPT instead of 20 CATs.

II. Experiment

Measurement of CPT (CAT) Activation Guinea pigs fasted for 25 hours are anesthetized under anesthesia and most connective tissue is removed. Immediately after filtering on filter paper, the organ is immediately placed in 60 ml of the following 30 preparations:

Sucrose (250 mM) Triethanolamine HCl (10 mM)

EDTA-K (ImM) 35

Adjust the pH to 7.45 using a 20% potassium hydroxide solution using an electric pH meter.

The liver is then cut with scissors into small pieces and washed twice or three times to remove any adherent blood. The liver pieces are then homogenized using a shredder and the resulting homogeneous material is made up to a final volume of about 20 ml. Centrifuge at 700 g for 15 minutes to isolate the mitochondria, collect the supernatant and continue for another 15 minutes.

The experimental arrangements were centrifuged at 9000 g. The precipitate is washed three times in the preparation medium and centrifuged again each time. The combined mitochondria thus obtained are finally suspended in the preparation medium. This mitochondrial suspension is used in all determinations.

Protein concentration was determined by the biuret method.

Determination of CPT activity

Test principle:

Pa 1 mitoyl carnitine (C ¹⁴ ) + CoASH Palmitoyl-CoA + carnitine (C ¹⁴ )

Determination of the CAT activity of carnitine palmitoyl-C ^l4 from happening ^{carnitine-C14} formation direction. Due to the known localization of CAT II on the inner mitochondrial membrane and the lack of permeability of CoASH, it is obvious that without the addition of this coenzyme, only CAT 11 can reach the inner mitochondrial CoASH pool. Under these conditions, therefore, only CAT II is measured for intact mitochondria.

However, when mitochondrial preparation is sonicated or CoASH is added to the incubation medium, the sum of CAT I and CAT II activity is determined.

The incubation medium has the following composition:

(final concentration in test)

KC1 120 mM kh _{2 after 4} 5 mM triethanolamine x 2 H ₂ O 20 mM EDTA K ₂ x 2H ₂ O 0.5 mM 1 maleate 0.5 mM saccharose 25 mM MgCl ₂ x 6H ₂ O 5 mM bovine albumin 5 mg / ml. The following substrates are (final concentration in the test): CoA 0.10 mM Palmitoil Carnit (C ¹⁴ ) 0.10 mM Test substance 0.01 mM Compound 25 and 0.05 mM 1-Phenyl-1-ethyl-biguanide

for the determination of CPT II and CPT I activity / ml /

Ink. material ^h 2 ° ' SoASlt Aayag mitochondr. palm. kara. HClO ^ Blind value 0.5 0.5 - - w 100% value 0.5 0.5 - - - 0.1 - CPT II O-Value 0.5 0.3 - - 0.1 0.1 0.1 control 0.5 0.3 - 0.1 0.1 0.1

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Table T / continued / h ₂ p

CoASll Material mito- palm.— HC1O, chondr. lanyard.

Ink.

anvae

material 0.5 0.2 - 0.1 0.1 0.1 0.1 material 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 control 0.5 0.2 0.1 - 0.1 0.1 0.1 material 0.5 0.1 0.1 0.1 0.1 0.1 0.1 material 0.5 0.1 0.1 0.1 0.1 0.1 0.1

to 0.5 ml Erlenmeyer flasks -

Pipette 0.5 ml of incubation medium and an appropriate volume of water, coenzyme A, the respective material and the mitochondrial suspension according to the experimental set-up described above. All probes are incubated for 10 to 30 minutes at 37 ° C and shaken at 100 rpm with the exception of zero, with a shaker. The null assay was immediately stopped by adding 0.1 mL of 70% HClO ₄ . Then, for each test run, except for 35 blank, 0.1 to 0.1 ml of palmitoyl carnitine ( ^C14 ) is pipetted over a 5 second time shift. Samples were incubated in a water bath at 37 ° C and 100 / min with shaking for 5 minutes, and then quenched with the same intervals from 0.1 to 0.1 ml of 40 70% HClO ₄ addition.

The contents of the incubation dishes were then poured into small plastic centrifuge tubes and centrifuged in a refrigerated centrifuge at 4 x 45 x 10 ³ / min.

Calculation of CAT activity:

II. T á b 1 ₌ ________ ^c PC Spec, activity x 6Ö x 436,1x0,5 '(DPM ,, - DPM. ,,) x,.,, Test o-values PC yield = -------- --- ~ --------------;

DPM ,,.,. ™, x T x c lOOzertek prot

Cpc ...... concentration of palmitoyl carnitine used [nMol / ml];

DPM ..... (bpm);

c _F mi ..... concentration of mitochondrial protein used (mg);

spec. special activity of palmitoyl carritin used [KBq / mgj;

T ..... incubation time (minutes);

yield ..... the carnitine (C ¹⁴ ) formed [nMol / min / mg / protein].

The results are summarized in the following table:

Effect of Compounds of Formula I on CPT I and CPT II on Isolated Guinea Pig Nytochondria

Material CPT I CPT II Conc. / mM / Average effect nMol / m / mg protein Difference j'ij Conc. / 'NM / Average effect mMol / m / mg protein The difference is l control NaCl 5.477 K NaCl 1,198 K The 13th 0,050 4.577 -16.4 0,050 .595 -50.3 The 13th 0,100 4.325 -21.0 0,100 0.520 -56.6

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II. Table / Continued /

CPT I '' CPT II

Material Conc. / aM / Average effect nMol / m / shirt protein, Difference /%/ Conc. / ηΜ / Average effect in mMol / m / mg protein Difference / -4 / control NaCl 5.527 X NaCl 1,571 X C 3 0,050 5.147 -6.9 0,050 1,130 2S, 1 control NaCl 5.406 NaCl 1,039 κ C 6 0,050 5.095 -5.8 0,050 0.734 -29.4 control NaCl 7.901 NaCl 1,450 X B 4 0,050 7.084 -10.3 0,050 0.813 -43.9 control NaCl 7.860 κ NaCl 1,155 κ 15 0,050 6.850 -1 2.9 0,050 0,204 -82.3 control NaCl 5.291 X NaCl 1,479 κ In Figure 14 0,050 4.160 -21.4 0,050 0.552 -62.7 control NaCl 8.024 κ NaCl 1,338 κ 17 0,050 6.761 -15.7 0,050 0.329 -75.4 control NaCl 5.543 X NaCl 1.123 κ D 6 0,020 5.391 -2.7 0,020 0.988 -12.0 control NaCl 5.661 κ NaCl 1,431 κ D 15 0,050 5.498 -2.9 0,050 1,417 -1.0 D 15 0,100 5.206 0,100 1,358 -5.1 control NaCl 6.512 κ NaCl 1,670 X D 14 0,050 4.771 -26.7 0,050 1,579 -5.5 D 14 0,100 4.165 -36.0 0,100 1,583 -5.2 control NaCl 5.133 κ NaCl 0.916 κ D 20 0,050 4.719 -8.1 0,050 0,880 -3.9 D 20 0,100 4.653 -9.7 0,100 0,762 -16.8 control NaCl 7.319 κ NaCl 1,119 κ D 19 0,050 6.548 -10.5 0,050 1,164 4.0

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12

II. Table / Continued /

CPT I '' CPT II

Material Conc. / MM / Mean effect nMol / m / mg protein, Difference /% / Conc. / NLA / Average effect in mMol / m / mg protein Difference /%/ control NaCl 4,559 NaCl 1,111 X D 12 o o5o 4,020 -11.8 0,050 1,127 1.4 D 12 0,100 3,545 -22.2 0,100 1,082 -2.6 control NaCl 6.533 NaCl 1,129 X D 59 0,050 5.575 -14.7 0,050 1.162 2.9 D 59 0,100 5,000 -23.5 0,100 1,116 -1.2 control NaCl 7.556 X NaCl 1,082 X D 16 0,050 7.448 -1.4 0,050 1,041 -3.8 D 16 0,100 7.215 -4.5 0,100 1,071 -1.0 control NaCl 5.502 X NaCl 1,177 X D 73 0,050 4.653 -15.8 0,050 1,156 -1.8 D 73 0,100 4.222 -23.3 0,100 1,140 -3.1 control NaCl 4.201 X NaCl 1,125 X D 107 0,050 3.756 -10.6 0,050 0,972 -15.1 D 107 0,100 3.429 -18.2 0,100 0.973 15.0 control NaCl 7.633 X NaCl 1,222 X D 142 0,050 7.392 -3.2 0,050 1,380 -3.0 D 142 0,100 7.271 -4.7 0,100 1,333 -6.3 control NaCl 8.396 NaCl 1,2S1 X D 134 0,100 7.994 -4.8 0,100 1,201 -6.3 control NaCl 2.929 X NaCl 1,191 X The 22 0,050 2,080 -17.6 0,050 0, S89 -25.4 control NaCl 7.090 X NaCl 1,480 X The 20th 0,050 5.987 -15.6 0,050 1,138 -23.1

Explanation:

x = see list of examples.

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Thus, the compounds of formulas I to V are useful in the treatment of cardiovascular diseases. However, they are mainly used in diseases that are associated with inadequate oxygenation of the heart (ischemia), such as heart failure, angina pectoris or myocardial infarction.

Thus, the preparation of further classes of compounds (compounds of the formula I-V known per se) for a new indication is an enrichment of pharmacy.

The present invention therefore relates to a process for the preparation of a pharmaceutical composition comprising a compound of formula (I) to (V).

Preferred halogen atoms are in each case fluorine, chlorine or bromine, especially chlorine.

Preferred straight chain alkylene chains include:

- (CH ₂ ) _k - where X = 1-5, -CH = CH-CH ₂ - and -C = C-CH ₂ -.

As branched groups, the following are particularly preferred:

-CH = C-CH ₂ - and -C = CH-CH ₂ II

CH ₃ ch ₃

Physiologically acceptable salts include, in particular, the alkali metal, alkaline earth metal and ammonium salts.

The following compounds are particularly preferred according to the invention:

A 1) 2- (Phenethylhydrazono) -propionic acid,

A 2) 2- (4-methoxyphenethylhydrazono) propionic acid,

A) 2- (4-Chloro-phenethyl-hydrazono) -propionic acid,

A 4) 2- (2- (p-tolyl) ethylhydrazono] propionic acid,

A 6) 2- (2-Methyl-phenethyl-hydrazono) -propionic acid,

A 7) 2- (4-Fluoro-phenethyl-hydrazono) -propionic acid,

12) sodium 2- (3-phenylpropylhydrazono) propionate,

13) sodium 2- (cinnamylhydrazono) propionate,

14) sodium 2- (2-methoxyphenethylhydrazono) propionate,

15) sodium 2- (β-methylcinnamylhydrazono) propionate,

16) sodium 2- (2-phenylpropylhydrazono) propionate,

17) sodium 2- (3-bromophenethylhydrazono) propionate,

A 19) 2- (Phenethylhydrazono) -propionic acid,

A 20) 2- (3-Methylcinnamyl) hydrazono] propionic acid,

A 21) 2 - [(2-Chloro-cinnamyl) -hydrazono] -propionic acid,

A 22) 2 - [(3-Chloro-cinnamyl) -hydrazono] -propionic acid,

A 23) 2 - [(4-Chloro-cinnamyl) -hydrazono] -propionic acid,

A 24) 2- [Z- (6-Methyl-cinnamyl) -hydrazone] -propionic acid,

A 25) 2- [E- (β-Methyl-cinnamyl) -hydrazone] -propionic acid,

A 26) 2- (2-m-tolyl) -ethylhydrazono] -propionic acid,

A 27) 2- (3-Methoxy-phenethyl-hydrazono) -propionic acid,

A) 2- (2-Chloro-phenethyl-hydrazono) -propionic acid,

A 29) 2- (4-phenyl-butyl-hydrazono) -propionic acid, A 31) 2- (4-phenyl-2-butenyl-hydrazono) -propionic acid,

A 32) 2- (4-phenyl-3-butenylhydrazone) -propionic acid,

A 33) 2- (3-Phenyl-butyl-hydrazono) -propionic acid, A 34) 2- (3-Phenyl-2-butenyl-hydrazono) -propionic acid,

A 35) 2- (2-Methyl-3-phenyl-propyl-hydrazono) -propionic acid,

B 2) 2- (isobutyl hydrazono) propionic acid,

B 4) 2- (propylhydrazono) -propionic acid,

B 8) 2- (isopropyl hydrazono) propionic acid, B 10) 2- (butyl hydrazono) propionic acid,

B 11) 2- (sec-butyl hydrazono) propionic acid, B 12) 2- (tert-butyl hydrazono) propionic acid, B 30) 2- (methyl hydrazono) propionic acid,

C 2) 2- [2- (2-ethoxyethoxy) ethylhydrazono] propionic acid,

C3) 2- (2-phenoxyethylhydrazono) -propionic acid, C4) 2- (3-phenoxypropylhydrazono) -propionic acid,

C 5) sodium 2- (2-phenoxypropyl hydrazono) propionate,

C 6) sodium 2- [2- (2-methoxyethoxy) ethylhydrazono] propionate,

D1) sodium 2- (2-methylallyloxyimino) propionate,

D 2) sodium 2- (2-methoxyethoxyimino) propionate,

D 3) sodium 2- (3-phenylpropoxyimino) propionate,

D 4) sodium 2- (2-phenoxyethoxyimino) propionate,

D 5) sodium 2- (2-cyclohexylethoxyimino) propionate,

D 6) 2- (2-p-tolyl-ethoxyimino) -propionic acid, D 7) 2- (2-phenylethoxy-imino) -propionic acid,

D 8) 2-hexyloxyiminopropionic acid,

D 9) 2-Octyloxyiminopropionic acid,

D 10) 2- (3-phenyl-2-propynyloxyimino) -propionic acid,

D 11) 2- (gamma-methyl-cinnamyloxyimino) -propionic acid,

D 12) 2-cinnamoyloxyiminopropionic acid,

D 13) 2- (β-methyl-cinnamyloxyimino) -propionic acid,

D 14) 2- (3-Chloro-cinnamoyloxyimino) -propionic acid,

D 15) 2- (2-Chloro-cinnamyloxyimino) -propionic acid,

D 16) 2- (4-Chloro-cinnamyloxyimino) -propionic acid,

D 17) 2- (allyl-oxyimino) -propionic acid,

D 18) 2- (4-Fluoro-cinnamoyloxyimino) -propionic acid,

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D 19) 2- (3-Trifluoromethyl-cinnamyloxyimino) -propionic acid,

D 20) 2- (3-methyl-cinnamyloxyimino) -propionic acid,

D 21) 2- (4-tert-Butyl-cinnamyloxyimino) -propionic acid,

D 22) 2- (3-methoxy-cinnamyloxyimino) -propionic acid,

D 23) 2- (2-methoxy-cinnamyloxyimino) -propionic acid,

D 24) 2- (5-Chloro-2-methyl-cinnamyloxyimino) -propionic acid,

D 25) 2- (5-Chloro-2-methoxy-cinnamyloxyimino) -propionic acid,

D 26) 2- [3- (1-naphthyl) -2-propenyloxyimino] propionic acid,

D 27) 2- (3,5-Dichloro-cinnamyloxyimino) -propionic acid,

D 28) 2- (5-Chloro-2-methoxy-p-methyl-cinnamyloxyimino) -propionic acid,

D 29) 2- (5-Bromo-2-methoxy-cinnamyl-oxyimino) -propionic acid,

D 30) 2- (5-Fluoro-2-methoxy-cinnamyloxyimino) -propionic acid,

D 31) 2- (2-Methoxy-5-trifluoromethyl-cinnamyloxyimino) -propionic acid,

D 32) 2- (2,5-Dimethoxy-cinnamyloxyimino) -propionic acid,

D 33) 2- (2-Methoxy-5-methyl-cinnamyloxyimino) -propionic acid,

D 39) 2- (cinnamyloxyimino) -3-fluoropropionic acid,

D 40) 3-chloro-2-cinnamyloxyiminopropionic acid,

D 42) 2-Cinnamyl-oxyimino-butyric 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 51) sodium 2- (4-phenylbutoxyimino) propionate,

D 57) 2-Cinnamyl-oxyiminopropionic acid,

D 59) 2- (3-Fluoro-cinnamyloxyimino) -propionic acid,

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

D 61) 2- [3- (4-Methyl-phenyl) -propoxyimino] -propionic acid,

D 62) 2- [3- (3-Chloro-phenyl) -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 71) 2- (4-Methyl-cinnamyloxyimino) -propionic acid,

D 72) 2- (3-tert-Butyl-cinnamoyloxyimino) -propionic acid,

D 73) 2- (3-Bromo-cinnamyloxyimino) -propionic acid,

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

D 87) 2- (β-Chloro-cinnamyloxyimino) -propionic acid,

D 106) 3-Fluoro-2- (3-phenyl-propoxyimino) -propionic acid,

D 107) 2- (3-Phenylpropoxyimino) butyric acid,

D 108) 2- [3- (3-Chloro-phenyl) -propoxyimino] -3-fluoro-propionic acid,

D 109) 2- [3- (3-Chloro-phenyl) -propoxyimino] -butyric acid,

Dili) 2- [3- (3-methyl-phenyl) -propoxyimino] -butyric acid,

D 118) 2- (3-Chloro-cinnamyloxyimino) -butyric acid, D 120) 2- (3-methyl-cinnamyloxy-imino) -butyric acid, D 131) 2- (2-n-propoxy) cinnamyl-hydroxyimino-butyric acid,

D 133) 2- [3- (3-Trifluoromethyl-phenyl) -propoxyimino] -propionic acid,

D 134) 2- (4-Methoxy-cinnamyloxyimino) -propionic acid,

D 136) 2- [3- (3-chlorophenyl) propoxyimino] pentanoic acid,

D 139) 2- [3- (3-methoxyphenyl) propoxyimino] butyric acid,

D 140) 2- [3- (3-Trifluoromethyl-phenyl) -propoxyimino] -butyric acid,

D 141) 2- (3-methylcinnamyloxyimino) butyric acid, D 142) 2- (3-Trifluoromethylcinnamyloxyiminobutyric acid) and the corresponding free acid forms and their corresponding forms. their physiologically acceptable salts.

Dosage forms suitable for use in the cardiovascular system according to the invention include conventional oral and parenteral dosage forms, e.g. tablets, capsules, dragees, syrups, solutions, suspensions, drops, suppositories, etc. come into consideration. Oral administration is preferred, but intravenous administration is also conceivable, for example in post-infarction treatment, to prevent the spread of the infarct nucleus.

Therefore, the present invention relates to a pharmaceutical composition comprising as active ingredient a compound of formula (IV), if present in the form for a new indication and having, in particular, appropriate instructions for use.

For the preparation of pharmaceutical compositions, the active ingredient is mixed with solid or liquid carriers and processed in the form desired. Solid carriers include starches, lactose, mannitol, methylcellulose. talc, highly dispersed silica, long chain fatty acids (e.g. stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, high molecular weight polymers (e.g., polyethylene glycols). Compositions suitable for oral administration may, if desired, contain flavoring and sweetening agents.

Water for injection is preferably used and may contain additives such as stabilizers, solubilizers and / or buffers which are customary in injection solutions, such as acetate or tartrate buffer, ethanol, compex 10197668 lex formers such as ethylene. -diamine tetraacetic acid and its non-toxic salts, or high molecular weight polymers (such as polyethylene oxide) for viscosity control.

The dosage may depend on various factors such as the route of administration, the species to be treated, the age and / or the individual condition. In humans, the daily dose will normally be 20-700 mg, preferably 100-400 mg / day, in 1 to 4 divided doses, based on about 70 kg body weight. However, much higher doses or lower doses than topical administration may be employed.

The term " ¹ * produced in a known manner, as used herein, encompasses procedures known in the art to the day of priority.

Claims (8)

PATENT CLAIMS A process for the preparation of alpha-keto-carboxylic acid hydrazines and oximes of the formula I in which Y is -NH- Z is a linear or branched alkylene group containing from 1 to 4 carbon atoms, R 1 is C 1 -C 4 alkyl, and R ₂ is C 1 -C 4 alkoxy substituted with C 1 -C 4 alkoxy, and their physiologically tolerated salts, characterized in that the active ingredient is prepared in admixture with conventional additives for the preparation of medicaments, into cardiovascular diseases. (E: July 11, 1985) 2. A process for the preparation of 2- (phenylalkylhydrazono) propionic acid derivatives of the general formula (II) R ₃ is halogen, C 1-4 alkoxy, C 1-4 alkyl, and X is a linear, saturated or unsaturated C 2 -C 4 alkylene group optionally substituted with a C 1 -C 4 alkyl group in the β or gamma position relative to the nitrogen atom, and their physiologically tolerated salts, characterized in that The active ingredient obtained is mixed with the usual additives for the preparation of medicaments to form a medicament for the prevention of cardiovascular diseases. (E: July 17, 1984) 3. A process for the preparation of the 2-hydrazono-propionic acid derivatives of the formula (III): R is a linear or branched C 1 -C 5 alkyl group and X represents a valence bond - for the preparation of pharmaceutical compositions containing physiologically tolerable salts thereof, characterized in that the active compound, which is prepared in a known manner, is mixed with the usual additives for the preparation of medicaments, to form cardiovascular diseases. (E: July 17, 1984) 4. A process for the preparation of pyrimidic acid hydrazines of the formula IV as an active ingredient of the formula R 'is phenyl or naphthyl, X is a group of formula A-B, wherein A is a nitrogen atom and B is attached to R 'and A is a straight-chain alkylene group having 2 to 4 carbon atoms and B is an oxygen atom - and their physiologically tolerated salts, characterized in that the active ingredient is prepared in a known manner by admixing the cardiovascular for the treatment of systemic diseases. (E: July 17, 1984) 5. A process for the preparation of a carboxylic acid oxime derivative of general formula (V) as an active ingredient R 'is phenyl or naphthyl which may be monosubstituted with C 1-4 alkyl, C 1-4 alkoxy, halogen, trifluoromethyl, A is a linear or branched, saturated or unsaturated alkylene chain having up to 5 carbon atoms, and R 1 is a C 1 -C 4 alkyl group and a physiologically tolerated salt thereof, characterized in that the active ingredient is prepared in a known manner by admixing it with the usual additives used in the preparation of the medicaments to form a cardiovascular medicine. (E: July 17, 1984) 6. The process according to claim 1, wherein the active ingredient is sodium 2- (cinnamylhydrazono) propionate, 2- (2-phenoxyethyl hydrazono) propionic acid, sodium 2- [2- (2-methoxyethoxy) ethyl hydrazono) propionate, 2- (propylhydrazono) -propionic acid, sodium 2- (β-methylcinnamylhydrazono) propionate, sodium 2- (2-methoxyphenethylhydrazono) propionate, sodium 2- (3-bromo) -phenethyl hydrazono) - propionate, 2- (2-p-distant 1-ethoxyimino) -propionic acid, 2- (4-chloro-cinnamyloxyimino) -propionic acid, 2- (2-chloro-cinnamyloxy-imino) -propionic acid, 2- (3-chloro-cinnamyloxy-imino) -propionic acid, 2- (3-methyl-cinnamoyloxyimino) -propionic acid, 2- (3-trifluoromethyl) -cinnamoyloxyimino-propanoic acid, -11197668 2-cinnamyl-hydroxyimino-propionic acid, 2- (3-Fluoro-cinnamyloxyimino) -propionic acid, 2- (3-bromo-cinnamyloxyimino) -propionic acid, 2- (3-phenyl-propoxyimino) -butyric acid, 2- (3-trifluoromethyl-cinnamyloxyimino) -butyric acid, 2- (4-methoxy-cinnamoyloxyimino) -propionates, 2 - [(3-chlorocinnamyl) hydrazono] propionic acid and / or For the preparation of pharmaceutical compositions containing 2 - [(3-methylcinnamyl) hydrazono] propionic acid, characterized in that the active ingredient, which is prepared in a known manner, is combined with the usual additives for the preparation of medicaments, to form cardiovascular disease medicaments. (E: July 11, 1985) 7. A process for the preparation of a pharmaceutical composition comprising 2- (3-phenylpropoxyimino) butyric acid as an active ingredient according to claim 5, characterized in that 10 of the active compounds obtained are mixed with the usual additives for the preparation of medicaments, and are converted into pharmaceutical preparations for cardiovascular diseases. (E: July 17, 1984)