BE845963A - VINYLOGUE AMIDRAZONES, PROCESS FOR THEIR PREPARATION AND MEDICINAL PRODUCT CONTAINING THE SAME - Google Patents

Description

       

   <EMI ID = 1.1>

  
1-hydrazinophthalazine (hydralazine), its blood pressure lowering properties! and its side effects are known
(Ehrhart / Ruschig: Arzneimittel, 2nd edition, Vol. 2, p. 278/79, Verlag Chemie, Weinheim / Bergstrasse, 1972). In German patent application DT-OS 2.145.359, hydralazine derivatives are described, namely hydrazones of the general formula A

  

 <EMI ID = 2.1>


  
 <EMI ID = 3.1>

  
in which R, R, R and R represent a hydrogen atom or

  
a lower alkyl residue, (-presenting ^ also antihypertensive properties in which the effect referred to as hydralazine syndrome; namely a rapid pronounced drop in blood pressure with a significant increase (in heart rate, is less marked but with however a slower onset of effect and a smaller increase in heart rate.

  
The present invention relates to novel amidrazone derivatives

  
 <EMI ID = 4.1>

  

 <EMI ID = 5.1>


  
in which :

  
B represents the group

  

 <EMI ID = 6.1>


  
R represents a substituent.! any other than hydrogen or one; part of a condensed ring,

  
R <1>, R <2> are identical or different and represent a hydrogen atom,

  
 <EMI ID = 7.1>

  
tituated or together represent an alkylene group optionally

  
 <EMI ID = 8.1> <EMI ID = 9.1>

  
aliphatic or alicyclic boné, optionally substituted, a phenyl or phenalkyl group optionally substituted or together represent an alkylene bridge optionally interrupted by a heteroatom,

  
their addition salts with cis / trans and syn / anti acids and isomers.

  
Examples of R substituents are halogen atoms, alkyl groups containing from 1 to 6 carbon atoms, preferably lower alkyl groups, alkoxy groups comprising.

  
 <EMI ID = 10.1>

  
optionally substituted phenyl groups as well as dialkylamino groups comprising from 1 to 6 carbon atoms, preferably dialkylamino groups where the alkyl residue is a lower alkyl residue.

  
In the case where R represents a condensed ring, the group:

  
 <EMI ID = 11.1>

  
which comprises at least ^ one- other-; carbocyclic or heterocyclic ring, in which at least 2 rings of the condensed ring system have at least

  
2 atoms in common. These ring systems can be optionally substituted, for example by halogen atoms, lower alkyl groups.

  
 <EMI ID = 12.1>. As well as by aliphatic and / or aromatic acyl groups. Examples for such remnants of a ring system are by <EMI ID = 13.1>

  
1,1-dioxide, 1,2-benzisothiazol-1,1-dioxide, pyrido-pyridazines, pyridazinobénzothiazines, pyridoindoles, pyrroloisoquinolines, triazinoindoles,

  
 <EMI ID = 14.1>

  
Fluorine, bromine or iodine and preferably chlorine are taken into account as halogen substituents.

  
 <EMI ID = 15.1>

  
straight or branched chain alkyl groups comprising from 1 to 4 carbon atoms, in particular those comprising one carbon atom, are included. Mention may be made, by way of examples, of the methyl, ethyl and propyl groups.

  
 <EMI ID = 16.1>

  
 <EMI ID = 17.1>

  
 <EMI ID = 18.1>

  
substituted within the meaning of the invention, those which include in any position, preferably '\ or 2 substituents, are taken into account. As substituents, mention may be made, inter alia, of halogen atoms,

  
for example fluorine and bromine, preferably chlorine, alkyl, alkoxy or alkylmercapto groups each comprising from 1 to 4 carbon atoms, the trifluoromethyl group or the nitro group. Examples of substituted phenyl groups are the groups: o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, m-bromophenyl, p-bromophenyl, p-fluorophenyl. m-tolyl, p-tolyl, 3,4-dichlorophenyl, 3-chloro-p-tolyl, m-trifluoromethylphenyl, p-nitrophenyl, m-nitrophenyl, p-methoxyphenyl, p-ethoxyphenyl, 3,4-dimethoxyphenyl, cumenyl, p-Butylmercaptophenyl, 3,4-

  
 <EMI ID = 19.1>

  
The p-halophenyl groups and most particularly the p-chlorophenyl group, the p-methoxyphenyl group and the p-tolyl group are preferred.

  
Suitable amino groups substituted by alkyl are preferably amino groups substituted by one or two lower alkyl groups, lower alkyl groups having the meanings given above, as well as morpholino, piperidino and pyrrolidino groups.

  
Examples of aliphatic acyl groups are those derived from aliphatic carboxylic acids, in particular acids. lower carboxylic acids containing up to 4 atoms of. carbon, by <EMI ID = 20.1>

  
: the. In addition, alkoxycarbonyl residues,

  
 <EMI ID = 21.1>

  
 <EMI ID = 22.1>

  
Suitable aromatic acyl residues are, for example, substituted benzoyl residues, in which the phenyl ring contains one or two substituents with the meanings indicated above, as well as preferably the unsubstituted benzoyl residue.

  
 <EMI ID = 23.1>

  
When R and R together form an alkylene group, it is a group (-CH -) in which n preferably has the meanings 2 4, in particular 3, which can be optionally substituted by one or deu:
lower alkyl groups, preferably methyl groups.

  
As aliphatic hydrocarbon groups come in line of

  
 <EMI ID = 24.1> Examples of saturated hydrocarbon residues are lower alkyl groups already mentioned above. Examples of unsaturated hydrocarbon residues are, for example, allyl, 2-butenyl, 2-propinyl- groups.

  
 <EMI ID = 25.1>

  
counts cycloalkyl radicals comprising from 3 to 7 carbon atoms, for example the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radical, among which those comprising 5 and in particular 6 carbon atoms are preferred.

  
Substituents for the hydrocarbon groups are taken into account lower alkoxy groups and amino groups disubstituted by lower alkyl in which the lower alkyl residue has the meaning already indicated above. Examples of such subs

  
 <EMI ID = 26.1>

  
, preferably the dimethylamino group in which these substituents on the lower alkyl groups are preferably chain end.

  
Considerable phenylalkyl groups include those including. the alkyl part contains from 1 to 4 carbon atoms, the phenyl residue. being in any position of the alkyl chain, preferably in <EMI ID = 27.1>

  
 <EMI ID = 28.1>

  
The phenylalkyl groups can also be substituted, inter alia, by halogen atoms such as fluorine, chlorine or bromine,

  
 <EMI ID = 29.1>

  
benzyl among which the monosubstituted derivatives are preferred.

  
 <EMI ID = 30.1>; is a group (-CH2) m where m means a number from 2 to 7, from <EMI ID = 31.1> <EMI ID = 32.1>

  
 <EMI ID = 33.1>

  
As addition salts with acids, recourse is had to the acids customary in the art, of which pharmacologically admissible salts are preferred, which are prepared with the aid of organic and inorganic acids.

  
 <EMI ID = 34.1>

  
tion with acids which are pharmacologically permissible for example soluble and insoluble salts such as hydrochloride, hydrobromide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate (2- (4-hydroxybenzoyl) -benzoate), fendizoate (o-

  
 <EMI ID = 35.1>

  
sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate (4,4'-diamino-stilben-2,2'disulfonate), embonate (1 , 1'-methylen-bis-2-hydroxy-3-naphthoate), metembonate, stearate, tosilate (p-toluenesulphonate), 2-hydroxy3-naphthoate, 3-hydroxy-2-naphthoate, mesilate ( methansulfonate) as well

  
 <EMI ID = 36.1>

  
acetic) etc.

  
A particularly preferred form of the invention relates

  
 <EMI ID = 37.1>

  

 <EMI ID = 38.1>


  
:in which

  
 <EMI ID = 39.1>

  

 <EMI ID = 40.1>
 

  

 <EMI ID = 41.1>

Q

  
 <EMI ID = 42.1>

  
 <EMI ID = 43.1>

  
lower or an optionally substituted phenyl group,

  
 <EMI ID = 44.1>

  
gene, a lower alkyl group, a phenyl group optionally substituted in the para position by chlorine or

  
together form a propylene group optionally centrally substituted with a lower alkyl, preferably methyl,

  
 <EMI ID = 45.1>

  
saturated or unsaturated aliphatic bony, optionally substituted in the terminal position by a lower alkoxy group or a dialkylamino group in which the alkyl residue is a lower alkyl residue, an alicyclic hydrocarbon group comprising from 5 to 6 carbon atoms, a phenyl or phenalkyl group comprising from 1 to 2 carbon atoms in the alkyl residue,

  
optionally substituted in the para position by chlorine, lower alkyl or lower alkoxy or together form a group

  
 <EMI ID = 46.1>

  
amino or dialkylamino in which alkyl is a lower alkyl residue,

  
 <EMI ID = 47.1> partially substituted,

  
 <EMI ID = 48.1>

  
phenyl,

  
 <EMI ID = 49.1>

  
 <EMI ID = 50.1>

  
phenyl,

  
s represents a number from 0 to 7, <EMI ID = 51.1>

  
Particularly preferred vinologic amidrazones are

  
 <EMI ID = 52.1>
 <EMI ID = 53.1>
 .in which

  
B represents groups

  

 <EMI ID = 54.1>


  

 <EMI ID = 55.1>


  
 <EMI ID = 56.1>

  
 <EMI ID = 57.1>

  
substituted in the para position by chlorine, lower alkyl or lower alkoxy,

  
 <EMI ID = 58.1> <EMI ID = 59.1>

  
 <EMI ID = 60.1>

  
 <EMI ID = 61.1>

  
lower alkoxy or a phenyl residue,

  
10 &#65533;

  
R - represents a lower alkyl group,

  
 <EMI ID = 62.1>

  
 <EMI ID = 63.1>

  
 <EMI ID = 64.1>

  
ethoxy or phenyl and the other substituents have the meanings indicated above.

  
A particularly preferred form of the invention relates

  
 <EMI ID = 65.1>
 <EMI ID = 66.1>
 .where <EMI ID = 67.1>

  
lower alkyl group or a phenyl group optionally substituted in the para position by chlorine, lower alkyl

  
 <EMI ID = 68.1>

  
tally substituted in para position by chlorine or

  
together form an optionally substituted propylene group

  
 <EMI ID = 69.1>

  
R and R are the same or different and represent a group

  
 <EMI ID = 70.1>

  
substituted in the final position by a lower alkoxy group or a lower dialkylamino group, an alicyclic hydrocarbon group comprising from 5 to 6 carbon atoms, a phenyl or phenalkyl group comprising from to 2 carbon atoms in the alkyl residue, optionally substituted in position para by chlorine, lower alkyl or lower alkoxy or

  
 <EMI ID = 71.1>

  
feels a number from 4 to 6 or a group -CH -CH -Y -CH -CH

  
 <EMI ID = 72.1>

  
Particularly preferred vinylogue amidrazones are those

  
 <EMI ID = 73.1>

  

 <EMI ID = 74.1>


  
' in which

  
 <EMI ID = 75.1>

  
a phenyl group,

  
 <EMI ID = 76.1>: as well as their addition salts with acids. Among the compounds of

  
 <EMI ID = 77.1> <EMI ID = 78.1>
-propenylidene) -hydrazino7-phthalazine and their addition salts with acids.

  
The hydrazones of the general formula A are hydrazine derivatives of aldehydes and ketones. The compounds according to the invention of

  
 <EMI ID = 79.1>

  
 <EMI ID = 80.1>

  
compounds of the general formula I by virtue of the principle of vinylogy (cf. in this regard H. Krauch, W. Kunz: Reaktionen der organ. Chemie, Dr. Alfred

  
 <EMI ID = 81.1>

  
vinylogues, that is to say, hydrazine derivatives of carboxylic acids, and as a result it is a totally chemically different class of compounds which has its own physical and chemical properties. This is expressed, for example, in the fact that the compounds of general formula 1 cannot be obtained from hydrazinoazâ- '

  
 <EMI ID = 82.1>

  

 <EMI ID = 83.1>


  
 <EMI ID = 84.1>
 <EMI ID = 85.1>
 <EMI ID = 86.1> <EMI ID = 87.1> <EMI ID = 88.1>

  
It should be noted in this regard that the cations of formula IV

  
 <EMI ID = 89.1>

  
38, 1371 (1973) and Ch. Reichardt, K. Halbritter, Angew. Chem. 87, 129 (1975) or Liebigs Ann. Chem. 1975, 470) so that it was unexpected and unforeseen

  
 <EMI ID = 90.1>

  
can be obtained. On the contrary, it was more likely that the cations of formula IV would be easily transformed with the monosubstituted hydrazines II with scission of a secondary ammonium salt.

  
 <EMI ID = 91.1>

  

 <EMI ID = 92.1>


  
 <EMI ID = 93.1>

  
 <EMI ID = 94.1>

  
 <EMI ID = 95.1>

  

 <EMI ID = 96.1>


  
 <EMI ID = 97.1>
 <EMI ID = 98.1>
  <EMI ID = 99.1>

  
optionally subsequently the salt obtained as a free base and / or as an addition salt with a pharmacologically acceptable acid.

  
As Z acid anions, among other things,

  
 <EMI ID = 100.1>

  
alkoxysulphonate anions, preferably the lower alkoxysulphonate anions; alkylsulfonate anions, preferably lower alkylsulfonate anions, arylsulfonate anions such as naphthalenesulfonate or phenylsulfonate anions, for example naphthalene-2-sulfonate anions

  
 <EMI ID = 101.1>

  
The reaction is carried out in usual inert aprotonic solvents, the oximinium salt of general formula IV preferably being produced in situ and reacted with the hydrazinoazaheterocyclic compounds (II). As inert solvents, mention may be made, for example, of aliphatic hydrocarbons such as hexane, ethane, octane, petroleum ether, light gasoline, halogenated hydrocarbons such as

  
 <EMI ID = 102.1>

  
is generally carried out without an increase in temperature. This does not exclude, however, that in particular cases it is possible to have recourse to a certain increase or decrease in temperature. Reaction temperatures

  
 <EMI ID = 103.1>

  
The reaction is generally carried out in a short time so that reaction times between 0.5 and 8, preferably between 2 and

  
 <EMI ID = 104.1>

  
The addition salts with the acids obtained after the reaction can be isolated as such from the reaction solutions by) -the conventional operating techniques such as filtration, decantation etc. They can also be transformed into free bases of the; general formula I after isolation or in reaction solutions: by treatment with basic reagents or their aqueous solutions such as ammonia, alkali metal hydrogencarbonate such as bicar? sodium bonate, alkali metal carbonate such as carbonate; sodium or potassium, alkali metal hydroxide such as hydroxide; sodium or potassium, alkali metal alkolates such as

  
 <EMI ID = 105.1>

  
 <EMI ID = 106.1>

  
free bases, for example by reaction with corresponding acids. in a suitable solvent. Such reactions are well known to specialists and do not require inventive measures. It is advantageous when the salts constitute the desired product of the process to start from compounds of the general formula II which already contain the desired anion at the end, in order to avoid further reactions. However, this does not exclude

  
that in special cases the addition salt with the acid which is

  
 <EMI ID = 107.1>

  
The starting products for the compounds to be used

  
according to the invention are known or can be prepared by methods known per se.

  
The preparation of the hydrazinoazaheterocyclic compounds II 'is carried out, for example, by the methods indicated in the following sources:

  
 <EMI ID = 108.1> such as lower alkyl esters of methanesulfonic acids; /

  
benzenesulfonics, p-toluenesulfonics, 2-naphthalenesulfonics; lower alkyl halides such as methyl iodide, ethyl iodide, isopropyl bromide, allyl bromide, chloride

  
 <EMI ID = 109.1>

  
from left below) or lower trialkylhalosilanes such as

  
trimethylchlorosilane, triethylchlorosilane, trimethylbromosilane, in inert aprotonic solvents at temperatures of the order of room temperature, for example -10 to +30 [deg.] C. Owing to the relatively low stability and the difficulty of obtaining oxyminium salts in the pure state, they are preferably prepared in situ and reacted without further purification.

  
The preparation of 3-aminoacolein III required as a starting material for preparing the oximinium IV salt is also known. It is carried out for example in the case where R represents a hydrogen atom according to the prescriptions of S.M. Makin, Abla Ahmed Ishmael, V.V. Yastrebov and K.I. Petrov (Zhur.org.Khim. 7, (1972) 2120-2124). Or F..Will:

  
 <EMI ID = 110.1>

  
 <EMI ID = 111.1>

  
by N.J. Léonard and J.A. Adamcik (J.Amer.Chem.Soc. 81 (1959) 595 et seq.).

  
The compounds of the invention exhibit valuable pharmacological properties .; they reduce blood pressure, as shown in tests in narcotized and hypertonic-awake rats.

  
 <EMI ID = 112.1>

  
 <EMI ID = 113.1>

  
therapeutic an acceleration of the heart rate, the compounds

  
 <EMI ID = 114.1>

  
do not have this disadvantage and are rather characterized by a reduction in heart rate. In addition, compared to prior art compounds, they are more easily tolerated as indicated by lethal dose determinations after a single oral dosage in mice, compared to the results of buteralazine. With regard to the properties, in particular the absence of increased heart rate; the compounds of the invention constitute a therapeutic advance;

  
 <EMI ID = 115.1>

  
and a desired enrichment of the state of the art.

  
The remarkable efficacy of the compounds of the invention allows their application in human medicine, the indications being particularly essential or secondary hypertonia of all degrees of severity.

  
The invention therefore also extends to a medicament suitable for example for the treatment of human diseases, in particular hypertension which is characterized by the content of one or more of the novel compounds of the general formula I and / or their salts. pharmacologically compatible.

  
Medicines with antihypertensive activity are prepared by methods known per se, these being used either as such or optionally in combination with suitable pharmaceutical carriers, vehicles or excipients. If the new pharmaceutical preparations additionally contain active substances, pharmaceutical carriers, diluents or excipients, the active substance content of these mixtures is between 0.1 to 99.5%, preferably from 0.5 to 95% by weight. total mixture weight.

  
In accordance with the principles of the invention, the active substances are applied in any suitable formulation provided that the establishment or maintenance of a sufficient blood level is achieved. This can be achieved, for example, by oral or parenteral dosage in suitable doses. Advantageously, the pharmaceutical preparation of the activated substance is in the form of a unit dose which corresponds to the desired dosage. A unit dose can consist, for example, of a tablet, a dragee, a capsule or a determined volumetric quantity of a powder, a granulated product, a solution, an emulsion or a suspension.

  
For the purposes of the present invention, the term "unit dose" is understood to mean a physically determined unit which contains an individual quantity of the active constituent - in combination with a pharmaceutical carrier, the content of which of active substance is a fraction or a multiple of. 'an individual therapeutic dose. An individual dose contains, for example, the amount of active substance which is suitable for an application and which

  
 <EMI ID = 116.1>

  
Daily. When for a therapeutic dosage, only one

  
 <EMI ID = 117.1>

  
with a break groove.

  
The pharmaceutical preparations according to the invention contain, when they are presented in the form of an individual dose and when they are intended. for example for human application, approximately 0.1 to 500 mg, preferably 0.5 to 100 mg and in particular from 1 to 50 mg of active substance.

  
In general, it has been found to be advantageous in human medicine that the active substance (s) for oral dosage are applied.

  
 <EMI ID = 118.1>

  
 <EMI ID = 119.1>

  
in the form of several, preferably 1 to 3 individual doses to achieve the desired results. The individual dosage corresponds to the active substance (s) in amounts of the order of about 0.001 to about 2.5, preferably 0.01 to 1.5, and in particular 0.05 to 0.5 mg / kg of body weight. In the case of parenteral treatment, for example intravenously, similar dosages can be used.

  
Therapeutic dosage of pharmaceutical preparation

  
 <EMI ID = 120.1>

  
bles, for example each time after the meal and / or in the evening. It may, however, be advantageous to deviate from the aforementioned dosages and this depending on the nature, body weight, age of the patient to be treated, the type

  
and the extent of the disease, the type of preparation and application of the drug as well as the length of time or interval over which the dosage is applied. It may be sufficient in some cases to apply a lower amount of active substance than indicated, while in other cases the indicated amounts of active substance must be exceeded. In the case of a controlled dosage at the start of the treatment, a smaller dose is applied which is gradually increased. When the desired reduction in blood pressure has been achieved ,. we return again to a lower dose. Determining the dose

  
and the optimal type of application whenever necessary for the active substance can be easily determined by the practitioner on the basis of his professional knowledge:

  
Pharmaceutical preparations generally consist of the active substances according to the invention and non-toxic, pharmaceutically compatible drug carriers which are introduced into the mixture or which serve as diluents and which are presented in solid, semi-solid or solid form. liquid or as a coating agent, for example in the form of a capsule, tablet coating, sachet or other packaging, for the therapeutically active component. A carrier can, for example, serve as an intermediate for the absorption of the drug by the body, as a formulation adjuvant, as a sweetener, as a taste corrector, as a colorant or as a preservative.

  
For oral application, we can use for example

  
to tablets, dragees, hard or soft capsules, for example gelatin, a dispersible powder, aggregates, suspensions, emulsions, solutions or aqueous or oily syrups.

  
The tablets may contain inert diluents such as for example calcium carbonate, calcium phosphate, sodium phosphate or lactose, granulating or dispensing agents such as for example corn starch or alginates, binders such as for example starches, gelatin or acacia gum and lubricants such as for example aluminum or magnesium stearate, talc or silicone oil. They may further be provided with a coating which may also be designed so that a delayed dissolution or absorption of the drug in the gastrointestinal tract is obtained and therefore is better tolerated or exerts a retarding effect.

   Gelatin capsules may contain the drug in admixture with a solid diluent eg calcium carbonate or kaolin or with an oily diluent eg olive, peanut or paraffin oil.

  
Aqueous suspensions may contain activating agents.

  
 <EMI ID = 121.1>

  
cellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth or acacia gum, dispersing agents or wetting agents, for example. polyoxyethylenestearate, heptadecaethyleneoxyketanol, polyoxyethylenesorbitol monooleate, polyoxyethylenesorbitan mono, oleate or lecithin, preservatives for example methyl or propyl hydroxybenzoate, flavor correcting agents, sweeteners, for example saccharose lactose, sodium cyclamate, dextrose, invert sugar syrup etc.

  
The oily suspensions may contain, for example, peanut, olive, sesame, coconut, paraffin and thickening agents, for example beeswax, hard paraffin, cetyl alcohol as well as sweeteners, taste correctors and antioxidants.

  
In the case of water-dispersible powders or aggregates, the pharmaceutical products can be mixed with dispersing agents or wetting agents, or suspending agents, for example those mentioned above, as well as with sweeteners. , taste correctors and colorings.

  
The emulsions may contain for example olive oil, peanuts or paraffin as well as emulsifying agents for example acacia gum, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylenesorbitan monooleate and sweeteners or taste correctors.

  
For parenteral drug application,

  
to aqueous suspensions, isotonic saline solutions or special solutions, sterile and injectable which contain dispersing agents or wetting agents and / or pharmacologically compatible diluents, for example propylene glycol or butylene glycol.

  
On the other hand, the compounds according to the invention constitute valuable intermediates for preparing symmetrical or asymmetric hydrazidines vinylogans which are among other things pharmacologically very active ...

  
The present invention therefore also extends to vinylogue hydrazidines, processes for their preparation and medicaments containing them. _

  
1-Hydrazinophthalazine (hydralazine), its blood pressure lowering effect and side effects are known (Ehrhart /

  
 <EMI ID = 122.1>

  
present for use in the therapy of hypertension.

  
Thus, the German patent application DT-OS 2 145 359 describes hydralazine derivatives, namely the hydrazone of the general formula M

  

 <EMI ID = 123.1>


  
 <EMI ID = 124.1>

  
antihypertensive drug, in which the course of the effect called hydralazine syndrome - a large and rapid drop in blood pressure with a marked acceleration in heart rate - is softened in that the onset of the effect is more slow and the increase in heart rate is less.

  
The present invention relates to novel symmetrical and asymmetric vinylogue hydrazidines of the general formula XIa or XIb.

  

 <EMI ID = 125.1>


  
in which E and F are the same or different and represent unsaturated azaheterocycles with one or more rings which, with incorporation of hydrazino groups, form an amidrazone system of the partial structure G

  

 <EMI ID = 126.1>


  
 <EMI ID = 127.1>

  
part of a condensed ring, as well as their cis / trans or syn / isomers
-anti, their tautomers and their addition salts with acids.

  
 <EMI ID = 128.1>

  
halogen atoms, lower alkyl groups, lower alkoxy groups, optionally substituted phenyl groups as well as lower dialkylamino groups.

  
 <EMI ID = 129.1>

  
the group

  

 <EMI ID = 130.1>


  
constitutes part of a heterocyclic ring system which still contains at least one further carbocyclic or heterocyclic ring, at least two rings of the condensed ring system having at least two carbon atoms in common. These ring systems can also be substituted, for example by halogen atoms, lower alkyl groups, -

  
 <EMI ID = 131.1>

  
Examples of such ring systems are those derived from the compounds: isoindole, isoquinoline, phthalazine, 2H-1,2,3-benzothiadia-

  
 <EMI ID = 132.1>

  
dazinobenzbthiazines, pyridoindoles, pyrroloisoquinolines, triazinoindoles.

  
As halogen substituents for the hydrazidines, fluorine, bromine and iodine, and preferably chlorine, are considered.

  
As lower alkyl groups of the hydrazidines according to the invention, straight or branched alkyl groups comprising from 1 to 4 carbon atoms, in particular 1 carbon atom, are taken into account. Mention may be made, by way of examples, of methyl, ethyl, propyl, butyl, isopropyl, sec.butyl and tert.butyl groups. Lower alkoxy groups contain the aforementioned alkyl groups and there may be mentioned, for example, the ethoxy, propoxy, isopropoxy, butoxy, sec.butoxy, tert.butoxy groups, in particular the methoxy group.

  
In addition to unsubstituted phenyl groups there can be

  
 <EMI ID = 133.1>

  
As substituents, mention may be made, inter alia, of halogen atoms, for example fluorine and bromine, preferably chlorine, alkyl, alkoxy or alkyl mercapto groups each comprising 1 to 4 carbon atoms, trifluoromethyl or nitro groups.

  
As amino groups substituted by alkyl for the hydrazidiries according to the invention come into consideration monoalkylamino or dialkylamino groups where alkyl is a lower alkyl residue, these having the meaning already indicated as well as the morpholino, piperidino, piperazino groups (optionally N-substituted lower alkyl) or pyrrolidino.

  
As aliphatic acyl groups for the hydrazidines according to the invention, mention may be made of acid residues derived from aliphatic carboxylic acids, preferably comprising up to 4 carbon atoms, for example the propionyl or butyryl residue, preferably the residue acetyl, as well as alkoxycarbonyl residues in which the alkoxy group has the meanings indicated above.

  
Suitable aromatic acyl radicals for the hydrazidines according to the invention are benzoyl radicals in which the phenyl radical contains one or two substituents having the meaning indicated above, as well as preferably the unsubstituted benzoyl radical.

  
...

  
As addition salts with acids of the hydrazidines according to the invention, the usual acids of the art of which

  
 <EMI ID = 134.1>

  
tion of which the inorganic or.organic acids customary in galenic application are used.: Thus, are suitable as addition salts with pharmacologically admissible acids, for example soluble salts

  
 <EMI ID = 135.1>

  
fate, acetate, citrate, gluconate, benzoate, 2- (4-hydroxybenzoyl) -benzoate, propionate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate,

  
 <EMI ID = 136.1>, bundled

  

 <EMI ID = 137.1>


  
 <EMI ID = 138.1>

  
 <EMI ID = 139.1>

  
 <EMI ID = 140.1> <EMI ID = 141.1>

  
a piperidino group,

  
 <EMI ID = 142.1>

  
lower or a phenyl group optionally substituted in the para position by a chlorine atom, a lower alkyl group. or a group

  
 <EMI ID = 143.1>

  
represents a lower alkyl or lower alkoxy group, or an optionally substituted phenyl or phenoxy group and t represents

  
 <EMI ID = 144.1>

  
R represents a lower alkyl or phenyl group,

  
 <EMI ID = 145.1>

  
 <EMI ID = 146.1>

  
as well as their isomers, their tautomers or their addition salts with acids.

  
Particular preference is given to the hydrazidines viny-

  
 <EMI ID = 147.1>
 <EMI ID = 148.1>
 <EMI ID = 149.1>

  
 <EMI ID = 150.1>

  

 <EMI ID = 151.1>


  
wherein

  
 <EMI ID = 152.1>

  
 <EMI ID = 153.1>

  
or 1-piperidinyl,

  
R23 represents a hydrogen atom, a chlorine atom or a group

  
 <EMI ID = 154.1>

  
as well as their isomers, their tautomers and their addition salts with

  
 <EMI ID = 155.1>

  
 <EMI ID = 156.1>

  
 <EMI ID = 157.1>

  
 <EMI ID = 158.1>

  

 <EMI ID = 159.1>


  
in which

  
R 23 &#65533; represents a hydrogen or chlorine atom,

  
as well as their isomers, their tautomers or their addition salts with acids.

  
Particularly preferred compounds are: 3- (4-chlorophthalazinyl-1) -hydrazono-1- (2-phthalazinyl- (1) -hydrazino) -propene,

  
 <EMI ID = 160.1>

  
hydrazino) -propene and their acid addition salts'.

  
The hydrazones of the general formula M are hydrazin derivatives:

  
 <EMI ID = 161.1>

  
according to the invention exhibit a certain structural analogy with the compounds of the general formula M. It should however be taken into account that the compounds of the general formula XI as a result of the principle of vinylogy (cf. in this regard H. Krauch, W. Kunz: Reaktioneh der organ Chemie, Dr. Alfred

  
 <EMI ID = 162.1>

  
vinylogues, i.e. hydrazine derivatives of vinyloglycarboxylic acids and as a result it is a completely chemically different class of compounds which exhibits its physical properties and

  
 <EMI ID = 163.1>

  

 <EMI ID = 164.1>


  
wherein

  
E has the meanings indicated above,

  
 <EMI ID = 165.1>. Optionally substituted aliphatic or alicyclic carbon, an optionally substituted phenyl or phenalkyl group or together form an alkylene bridge optionally interrupted by. ' heterotoma, / compounds of the formula XI may be formed. On the contrary, it was to be expected that the hydrazine derivatives of type XII would react with 3-aminopropenales (XIII) either by giving vinylogue amidrazones of the general formula XIV

  

 <EMI ID = 166.1>


  
in which R 28 and R29 have the meanings indicated above or give corresponding substituted pyrazole derivatives XV

  

 <EMI ID = 167.1>


  
in which E has the meanings indicated above (see in this regard the chapter pyrazole in R.C. Elderfield, Heterocyclic Compounds,

  
 <EMI ID = 168.1>

  
The present invention also relates to a process for the preparation of vinylogue hydrazidines of the general formula XI which is characterized in that it reacts

  
la) a hydrazinoazaheterocycle of the general formula XII

  

 <EMI ID = 169.1>


  
in which E has the meaning indicated above with a 3-aminopropenal of formula XIII

  

 <EMI ID = 170.1>


  
 <EMI ID = 171.1>

  
 <EMI ID = 172.1>

  
addition with pharmacologically admissible acids or vice versa,. in a conventional manner, ..

  
or b) by reacting a hydrazinoazaheterocycle of the general formula- <EMI ID = 173.1>

  

 <EMI ID = 174.1>


  
 <EMI ID = 175.1>

  
 <EMI ID = 176.1>
 <EMI ID = 177.1>
  <EMI ID = 178.1>

  
and 'optionally then transforms the free base obtained into its addition salt with pharmacologically admissible acids or vice versa, in a conventional manner.

  
 <EMI ID = 179.1>

  
consider lower alkyl groups and their unsaturated analogues. Examples of saturated hydrocarbon groups are the lower alkyl groups already mentioned; examples that may be mentioned for unsaturated hydrocarbon residues allyl, 2-butenyl, 2-propinyl.

  
 <EMI ID = 180.1>

  
consideration is given to cycloalkyl radicals containing 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals, those having 5 and in particular 6 carbon atoms being preferred.

  
As substituents for the hydrocarbon groups, consideration may be given to lower alkoxy or lower dialkylamino groups, in which lower alkyl has the meaning already indicated above. Examples of such substituents are ethoxy, propoxy, isopropaxy, butoxy, and preferably methoxy or alternatively diethylamino, dipropylamino; dibutylamino, preferably dimethylamino, these substituents preferably being in the terminal position in the lower alkyl groups.

  
 <EMI ID = 181.1>

  
those in which the alkyl chain has 1 to 4 carbon atoms, the phenyl residue being in any position on the alkyl chain, preferably

  
 <EMI ID = 182.1>

  
 <EMI ID = 183.1>

  
phenethyl and in particular the benzyl residue being preferred. The phenylalkyl groups can be optionally substituted, inter alia, by halogen atoms such as fluorine, chlorine or bromine, alkyl or alkoxy groups comprising from 1 to 4 carbon atoms. Mention may be made, by way of examples, of p-chlorobenzyl, m-chlorobenzyl, p-bromobenzyl, o-fluorobenzyl, p-fluorobenzyl, p-methoxybenzyl, p-methylbenzyl groups,

  
 <EMI ID = 184.1>

  
monosubstituted are preferred.

  
 <EMI ID = 185.1>

  
is a group (-CH) for which u means a number of. 2 to 7, from

  
2 u preferably 4 to 6, in particular 5. When the alkylene bridge is interrupted

  
 <EMI ID = 186.1>

  
 <EMI ID = 187.1>

  
 <EMI ID = 188.1>

  
or different and signify a number from 1 to 3, preferably 2.

  
In a preferred embodiment, R28 and R29 represent lower alkyl groups or together represent, with inclusion of the nitrogen atom, a piperidino or morpholino group.

  
In a preferred embodiment, one of the participants in the reaction, namely XII or XIII and XIV or XVI respectively, is used in the form of an addition salt with the acids of a protonogenic acid HL where Le) represents the anion of an inorganic or organic acid. Among others, mono, bi or trivalent anions, among which the chloride, methanesulfonate or benzenesulfonate anions are preferred. In particular, the hydrazinoazaheterocycles

  
 <EMI ID = 189.1>

  
The reactions according to the procedure a) or b) are carried out in usual inert solvents, the components being mixed with each other in any order and stirred until the reaction comes to an end. As inert solvents, mention may be made, for example, of halogenated hydrocarbons, such as methylene chloride, chloroform,

  
 <EMI ID = 190.1> b) are carried out in general without an increase in temperature, this however not excluding a certain increase or reduction in temperature in particular cases. The reaction temperatures are generally <EMI ID = 191.1>

  
The reaction is generally carried out in a very short time, from. so that reaction times between 0.5 and 8, preferably between 2 and 5 hours, should be considered sufficient.

  
The addition salts with acids obtained after the reaction can be isolated as they are from the reaction solutions by conventional operating techniques known to the practitioner such as filtration, decantation, etc. They can also be transformed into

  
 <EMI ID = 192.1>

  
 <EMI ID = 193.1>

  
 <EMI ID = 194.1>

  
 <EMI ID = 195.1>

  
ethyl-dicyclohexylamine; it is particularly advisable to work in the absence of water. The addition salts with pharmacologically acceptable acids are optionally prepared from the free bases, for example by reaction with corresponding acids in a suitable solvent. Such reactions are well known to specialists.

  
 <EMI ID = 196.1>

  
Salts constitute the desired product of the process from compounds of the general formula XII- which already contain the desired anion in the final product, to avoid further reactions. This does not exclude cep: - not that in particular cases, the addition salt with the acid qu:
is desired either prepared from the free base or by transsalification.

  
 <EMI ID = 197.1>

  
the invention are known or can be prepared by methods known per se.

  
 <EMI ID = 198.1>

  
XVI which are preferably implemented, for example, by the methods indicated in the following sources:

  
3-hydrazinoisoindole: US Patent 3,919,202; 1-hydrazinoisoquinoline:
GB patent 710,047; 1-hydrazinophthalazine: J. Druey and B.H. Ringier, Helv Chim. Acta 34, 195-210 (1951); 3-hydrazino-pyridazine: E. Bellasio et.al

  
 <EMI ID = 199.1>

  
 <EMI ID = 200.1>

  
 <EMI ID = 201.1>

  
The preparation of 3-aminoacolein XIII is known. It is carried out for example according to the prescriptions of S.M. Makin, Abla Ahmed

  
 <EMI ID = 202.1>

  
 <EMI ID = 203.1>

  
21247 or F. Wille and L. Saffer / Liebigs Ann. Chem. 568, 39 (1950) 7 '.

  
The preparation of amidrazones XIV is described in Luxembourg patent n [deg.] 73-350 as well as in the present patent application.

  
The hydrazidines according to the invention are able to remarkably complex heavy metals, in particular those of the 1st, 2nd and 6th to 8th subgroup of the periodic system of the elements. They are therefore suitable, for example, for separating or precipitating these metals in industrial waste water or black water.

  
The hydrazidines of the invention also exhibit valuable pharmacological properties; they especially reduce blood pressure, as well as tests on narcotized and hypertonic rats

  
awake indicate it. While hydralazine and the compound of German patent application DT-OS 2 145 359 have the drawback that at therapeutic doses they cause an acceleration of the heart rate, the hydrazidines according to the invention - for example 3- / Tphtala-

  
 <EMI ID = 204.1>

  
not this disadvantage and are characterized rather by a reduction in heart rate. ' In addition, compared to the compounds of the state of the art, they are more easily tolerated as indicated by the determinations of the lethal dose 50 (LD 50) after a single oral dosage in mice, compared to the results of the hydralazine. As regards the properties, in particular the absence of an increase in heart rate, the compounds of the invention constitute a theoretical advance.

  
 <EMI ID = 205.1>

  
. The remarkable effectiveness of the hydrazidines of the invention allows their application in human medicine, the 'indications being particularly essential or secondary hypertonia of all degrees <EMI ID = 206.1>

  
The invention therefore also extends to a medicament suitable

  
 <EMI ID = 207.1>

  
hypertension which. is characterized by the content of one or more of the new compounds of the general formula XI and / or their pharmacological salts.

  
 <EMI ID = 208.1>

  
Medicines with antihypertensive activity are prepared by methods known per se, these being used either as such or optionally in combination with suitable pharmaceutical carriers, vehicles or excipients. If the new pharmaceutical preparations additionally contain active substances, pharmaceutical carriers, diluents or excipients, the active substance content of these mixtures is between 0.1 to 99.5%, preferably from 0.5 to 95% by weight. total mixture weight.

  
In accordance with the invention, the active substances are applied in any suitable formulation provided

  
that the establishment or maintenance of a sufficient blood level is achieved. This can be achieved, for example, by oral or parenteral dosage in suitable doses. Advantageously, the pharmaceutical preparation of the active substance is in the form of a unit dose which corresponds to the desired dosage. A unit dose can consist, for example, of a tablet, a dragee, a capsule or a determined volumetric quantity of a powder, a granulated product, a solution, an emulsion or a suspension.

  
For the purposes of the present invention, the term “unit dose” is understood to mean a physically determined unit which contains an individual quantity of the active constituent in combination with a pharmaceutical carrier, the active substance content of which is a fraction or a multiple of an individual dose therapeutic. An individual dose contains, for example, the amount of active substance which is suitable for an application and which is generally all, half, one third or one quarter of the daily dose. When, for a therapeutic dosage, only a fraction such as half or a quarter of a unit dose is used, this unit dose is preferably scored, for example in the form of a tablet with a rupture groove.

  
The pharmaceutical preparations according to the invention contain, when they are presented in the form of an individual dose and when they are intended for example for human application, approximately 0.1 to

  
500 mg, preferably 0.5 to 100 mg and in particular from 1 to 50 mg of active substance.

  
In general, it has been found to be advantageous in human medicine that the active substance (s) for oral dosage are applied at a daily dose of about 0.001 to about 5, preferably 0.01 to 2, in particular 0, 05 to 1 mg / kg of body weight, optionally as several, preferably 1 to 3 individual doses to achieve the desired results. The individual dosage corresponds to the active substance (s) in amounts of the order of approximately 0.001 to approximately, 2.5, preferably 0.01 to 1.5, and in particular 0.05 to 0.5 mg / kg body weight. In the case of parenteral treatment, for example intravenously, similar dosages can be used.

  
Therapeutic dosage of pharmaceutical preparation

  
can be done once to four times a day at fixed or variable times, for example each time after a meal and / or in the evening. It may however be advantageous to deviate from the aforementioned dosages and this depending on the nature, the body weight, the age of the patient to be treated, the type

  
and the extent of the disease, the type of preparation and application of the drug as well as the length of time or interval over which the dosage is applied. In some cases it may be sufficient to apply a lower amount of active substance than indicated, while in other cases the indicated amounts of active substance must be exceeded. In the case of a controlled dosage at the start of the treatment, a smaller dose is applied which is gradually increased. When the desired reduction in blood pressure has been achieved, it will again revert to a lower dose.

  
The determination of the optimum dose and type of application whenever necessary for the active substance can be easily determined by the practitioner on the basis of his professional knowledge.

  
Pharmaceutical preparations generally consist of

  
by the active substances according to the invention and non-toxic, pharmaceutically compatible drug carriers which are introduced into the mixture or which serve as diluents and which are provided in a solid, semi-solid or liquid form or as a coating agent, for example in the form of a capsule, tablet coating, sachet or other packaging, for the therapeutically active component. A support can

  
for example serving as an intermediate for absorption of the drug by the body, as a formulation adjuvant, as a sweetener, as a taste corrector, as a colorant or as a preservative.

  
For oral application, we can use for example

  
to tablets, dragees, hard or soft capsules, for example gelatin, a dispersible powder, aggregates, suspensions, emulsions, solutions or aqueous or oily syrups.

  
The tablets may contain inert diluents such as for example calcium carbonate, calcium phosphate, sodium phosphate or lactose, granulating or dispensing agents such as for example corn starch or alginates, binders such as for example starches, gelatin or acacia gum and lubricants such as for example aluminum or magnesium stearate, talc or silicone oil. They can further be provided with a coating which can also be designed so that a delayed dissolution or absorption of the drug in the gastrointestinal tract is obtained and therefore is better tolerated or exerts a retarding effect.

   Gelatin capsules may contain the drug in admixture with a solid diluent, for example calcium carbonate or kaolin, or with an oily diluent, for example olive, peanut, or paraffin oil.

  
Aqueous suspensions may contain activating agents.

  
in suspension, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth or acacia gum, dispersing agents or wetting agents, for example polyoxyethylenestearate, heptadecaethyleneoxyketanol, polyoxyethylenesorbitol monooleate, polyoxyethylenesorbitan monooleate or lecithin, preservatives, for example methyl or propyl hydroxybenzoate, taste correcting agents, sweeteners, for example sucrose, lactose, cyclamate sodium, dextrose or invert sugar syrup.

  
The oily suspensions may contain, for example, peanut, olive, sesame, coconut, paraffin and thickening agents, for example beeswax, hard paraffin, cetyl alcohol as well as sweeteners, taste correctors and antioxidants.

  
Water-dispersible powders or aggregates may contain the pharmaceuticals in admixture with dispersing agents or wetting agents, or suspending agents.

  
for example those mentioned above, as well as with sweeteners, flavor correctors and colorants.

  
The emulsions can contain for example olive oil, peanuts or paraffin as well as emulsifying agents for example acacia gum, tragacanth, phosphatides, sorbitan monooleate, monooleate of polyoxyethylenesorbitan and sweeteners or taste correctors.

  
For parenteral drug application,

  
to aqueous suspensions, isotonic saline solutions or special solutions, sterile and injectable which contain dispersing agents or wetting agents and / or pharmacologically compatible diluents, for example propylene glycol or butylene glycol.

  
 <EMI ID = 209.1>

  
Other active constituents that may be mentioned, for example, are other antihypertensives, diuretics, saluretics, alkaloids, etc., as well as dihydralazine, mefrudise, clopamide, spironolactone, chlor.othalidone, furosemide, polythiazide, hydrochlorothiazide, reserpine, dihydroergocristine, rescinamine and the overall alkaloid Rauwolfia etc.

  
The pharmacological properties of the compounds according to the invention were studied according to conventional methods using the compounds which follow as examples of compounds used:

  
 <EMI ID = 210.1>

  
Tests indicate that:

  
1. The compounds according to the invention reduce, during an i.v. dosage the

  
blood pressure of narcotized rats, partially more strongly and more consistently than dihydralazine and overall more markedly than budralazine.

  
2. The systolic blood pressure of awake genetic hypertonic rats fell after a single daily distribution over 6 days, the maximum decrease being obtained when D after 2 days, when dihydralazine was administered, A and B after 3 days. and when C is administered over 6 days. Unlike dihydralazine which increases the heart rate of animals, this decreases when the products studied are administered. This observation is important. practice because the heart rate increasing effect of dihydralazine is indicative of a general hyperdynamic circulatory phenomenon which limits the clinical value of

  
this product (cf. S. Goodman and A. Gilman .: "The pharmacological basis

  
 <EMI ID = 211.1>

  
1975) ... '-'

  
3. Lethal doses after a single oral administration (measured for

  
rats) are greater than 500 mg / kg indicating that the product according to

  
 <EMI ID = 212.1>

  
The results of the various tests carried out are included in the tables which follow.

  
Table I

  
 <EMI ID = 213.1>

  
narcotized rats (groups of 6 animals).

  

 <EMI ID = 214.1>


  
Table II

  
Influence on systolic blood pressure and heart rate in genetic hypertonic rats (groups of 8 animals each) during

  
 <EMI ID = 215.1>

  

 <EMI ID = 216.1>


  
The invention will be described in more detail by way of illustration.

  
 <EMI ID = 217.1>

  
Decomp. means decomposition and the temperature indications are given

  
 <EMI ID = 218.1>

Example 1

  
a) To 205.8 g of 3-dimethylamino-acrolein (Pb. 89-91 [deg.] / 1) is added dropwise with stirring and cooling 238 g of dimethyl sulfate.

  
After the addition is complete, the mixture containing the methoxysul-

  
 <EMI ID = 219.1>

  
still stirred overnight.

  
The mixture is diluted with 2 liters of anhydrous methylene chloride.

  
While cooling to 10 [deg.] C, 350 g of 4-chloro-1hydrazinophthalazine are added per portion. After the addition is complete, the reaction mixture is further stirred for 4 hours at room temperature then the red-orange precipitate is filtered off with suction and washed with methylene chloride. The mother liquors are concentrated under vacuum at
20 [deg.] C maximum; the residue is taken up in approximately 100 ml of methylene chloride, cooled in an ice bath and again filtered by suction. After drying under vacuum, a total of 650 g (93.2% of

  
 <EMI ID = 220.1>

  
phthalazine in the form of methoxysulphate, Pf. 167-168 [deg.].

  
This methoxysulfate is dissolved in 1.5 liters of methylene chloride and reacted with stirring with 1 liter of ice-cold water and 100 ml.

  
 <EMI ID = 221.1>

  
methylene is separated, dried over sodium sulphate and concentrated in vacuo at 20 to 30 [deg.] to about 1/3 of the initial volume. This causes the

  
 <EMI ID = 222.1>

  
Pf. 152 [deg.].

  
b) 3-dimethylamino-acrolein and dimethyl sulphate are reacted as indicated above. After dilution with methylene chloride and addition of 4-chloro-1-hydrazino-phthalazine, 1 liter of ice-cold water and 100 ml of a 25% aqueous ammonia solution are introduced after 3 hours, over 30 minutes and shaking.

  
The phase containing the methylene chloride is separated by suction, evaporated in vacuo and the residue is dried in vacuo. Yield in

  
 <EMI ID = 223.1>

Example 2

  
Analogously to Example 1, by reaction of 3-piperidino-acrolein
(Pf. 32-33 [deg.]) And dimethyl sulfate, the methoxysulfonate was prepared <EMI ID = 224.1>

  
 <EMI ID = 225.1>

Example 3

  
Analogously to Example <1>, there was obtained by reaction of 3-morpholino-acrolein (mp. 69-70 [deg.]) And diethyl sulfate, ethoxysulfonate

  
 <EMI ID = 226.1>

  
phthalazine. Yield: 28.1% of theory; Pf. 127 [deg.].

Example 4

  
In a manner analogous to Example 1, the following were obtained by reaction of 3-diethylamino-acrolein (Pb. 110-112 [deg.] / 2) and methyl p-toluenesulphonate, the

  
 <EMI ID = 227.1>

  
propenylidene) -hydrazino7-phthalazine. Yield: 58.4% of theory; Pf. 134 [deg.].

Example 5

  
Analogously to Example 1, the reaction of 3-diallyl-

  
 <EMI ID = 228.1>

  
tion thereof with 4-chloro-1-hydrazino-phthalazine as well as a

  
 <EMI ID = 229.1>

  
propargyl alcohol and manganese dioxide in benzene at 20 [deg.] C; Efficiency 56.3% -

Example 6

  
Analogously to Example 1, was prepared by reaction of 3-di-npropylamino-acrolein (Péb. 1610/12) and methyl methanesulfonate,

  
 <EMI ID = 230.1>

  
Pf. 83 [deg.].

  
3-Di-n-propylamino-acrolein is prepared by reacting di-n-propylamine, propargyl alcohol and manganese dioxide in benzene at 20 [deg.]. Yield 84.0%.

Example 7

  
In a manner analogous to Example 1, by reaction of 3-di-nbutylamino-acrolein (Pb. 170 [deg.] / 10) and methyl benzenesulfonate, the

  
 <EMI ID = 231.1>

  
aminopropenylidene) -hydrazino7-phthalazine. Yield: 48.6% of theory; Pf. 75 [deg.].

  
 <EMI ID = 232.1>

  
propargyl alcohol and manganese dioxide in benzene at room temperature; Yield 80.0

Example 8

  
Analogously to Example 1, 3-N- was prepared by reaction

  
 <EMI ID = 233.1>

Example 9

  
Analogously to Example 1, 1-dimeric acid was prepared by reaction.

  
 <EMI ID = 234.1>

  
lidino-5,5-dimethyl-cyclohex-1-en-3-one (Pf. 128 [deg.]) with dimethyl sulfate, / 3-methoxy-5,5-dimethyl-cyclohex-2- methoxysulfonate enylidene- (1) 7-pyrrolidinium and by reaction thereof with 4-chloro-1hydrazino-phthalazine, as well as further processing according to b), 1-pyrrolidino-5,5-dimethyl-cyclohex -1-en-3-on - (4-chloro-phthalazinyl-1) hydrazone. Yield: 37.1% of theory; Pf. 197-198 [deg.].

  
1-Pyrrolidino-5,5-dimethyl-cyclohex-1-en-3-one is prepared by heating a mixture of dimedone and piperidine in benzene with separation of water. Yield: 92.1%.

Example 11

  
In a manner analogous to Example 1, by reaction of 3-diisopropylamino-accolein (Pb. 98 [deg.] / 0.2) and ethyl bromide, the bromide was prepared.

  
 <EMI ID = 235.1>

  
hydrazino7'-phthalazine. Yield: 75.2% of theory; Pf. 160 [deg.].

  
3-Diisopropylamino-acrolein is prepared by reacting diisopropylamine, propargyl alcohol and manganese dioxide in benzene

  
at room temperature, Yield 66.4

Example 12

  
Analogously to Example 1, was prepared by reaction of 3-diethylamino-3-p-chlorophenyl-acrolein (Pf. 79 [deg.]) With methanesulfonate

  
 <EMI ID = 236.1>

  
hydrazino-phthalazine as well as a subsequent treatment according to a) methane-

  
 <EMI ID = 237.1>

  
hydrazino7-phthalazine. Yield: 69.2% of theory; mp. 172 [deg.].

  
 <EMI ID = 238.1>

  
with stirring with an ice-cooled saturated solution of sodium hydrogencarbonate. The chloroform phase is separated; dried over sodium sulphate and concentrated in vacuo to half the volume and a practically identical amount of cyclohexane is added thereto. This causes the

  
 <EMI ID = 239.1>

  
3-p-chlorophenyl-3-chloro-acrolein with excess diethylamine in the

  
 <EMI ID = 240.1> .1 ..

Example 13

  
Analogously to Example 1, 3-N- was prepared by reaction

  
 <EMI ID = 241.1>

  
67.9% of theory; Pf. 138 [deg.].

  
3-N-benzyl-N-methylamino-acrolein is obtained by reacting benzylmethylamine, propargyl alcohol and manganese dioxide in the

  
 <EMI ID = 242.1>

Example 14

  
Analogously to Example 1, the reaction of 1-

  
 <EMI ID = 243.1>

  
 <EMI ID = 244.1>

  
as well as a subsequent treatment according to b), 1-diethylamino-cyclohex1-en-3-on- (4-chlorophthalazinyl-1) -hydrazone. Yield: 55.3% of theory; Pf. 162-163 [deg.].

  
1-Dimethylamino-cyclohex-1-en-3-one is prepared by the reaction of cyclo-

  
 <EMI ID = 245.1>

  
 <EMI ID = 246.1>

Example 15

  
Analogously to Example 1, the reaction of 3-

  
 <EMI ID = 247.1>

  
phthalazine. Yield: 53.7% of theory; Pf. 113 [deg.].

  
 <EMI ID = 248.1>

  
bis- (2-methoxyethyl) -amine, propargyl alcohol and man dioxide

  
 <EMI ID = 249.1>

Example 16

  
Similarly to Example 1, 3-N- was prepared by reaction

  
 <EMI ID = 250.1> <EMI ID = 251.1>

  
nylidene- (1) 7-ammonium and by reaction thereof with 4-chloro-1hydrazino-phthalazine as well as a subsequent treatment according to b), 4-

  
 <EMI ID = 252.1>

  
lazine. Yield: 53.9% of theory; Pf. 168 [deg.].

  
3-N-Cyclohexyl-N-isopropylamino-acrolein is prepared by reacting cyclohexylisopropylamine, propargyl alcohol and manganese dioxide in benzene at room temperature. Yield: 81.0%.

Example 17

  
Analogously to Example 1, - 3-N-N-methyl-anilino-acrolein (Pb. 145-147 [deg.] / 3) and methyl chloride were prepared by reaction,

  
 <EMI ID = 253.1>

  
Pf 146-148 [deg.].

  
This hydrochloride is suspended in methylene chloride, suitably extracted with ice-cold N sodium hydroxide solution and the organic phase is separated. After drying on carbonate

  
 <EMI ID = 254.1>

  
anilino-propenylidene) -hydrazino7-phthalazine from Pf. 88-90 [deg.].

Example 18

  
 <EMI ID = 255.1>

  
with ice-cooling and stirring, 10.8 g of trimethylchlorosilane. After 30 minutes of stirring, the solution containing the chloru-

  
 <EMI ID = 256.1>

  
(1) 7-ammonium, 9.7 g of 4-chloro-1-hydrazino-phthalazine and then stirred for an additional 2 hours. The mixture is left to stand overnight, away from moisture. The finely crystallized precipitate is filtered.

  
 <EMI ID = 257.1>

  
at 60 [deg.] .. After clarification with activated carbon, ether is added to the solution which causes the separation of the hydrate from the hydrochloride.

  
 <EMI ID = 258.1>

  
After drying under vacuum, 15.0 g (70.8% of theory) of pro-

  
 <EMI ID = 259.1>

  
 <EMI ID = 260.1>

  
reaction of N- (2-dimethylaminoethyl) -N-methylamine, propargyl alcohol and manganese dioxide in benzene at room temperature.

  
 <EMI ID = 261.1>

Example 19

  
Analogously to Example 18, the reaction of 3-N-methyl-

  
 <EMI ID = 262.1>

  
propenylidene) -hydrazino7-phthalazine from which the free base is obtained by reaction with a saturated aqueous solution of potassium carbonate and by a complementary reaction with 1, methanesulfonic acid in a mixture of methylene chloride / cyclohexane, the hydrate of dimethane-

  
 <EMI ID = 263.1>

  
phthalazine. Yield: 23.4% of theory; Pf. 154 [deg.].

Example 20

  
10.0 g of 4-phenyl-1-hydrazino-phthalazine hydrochloride is mixed with 30 ml of dimethyl sulfoxide and reacted with 1.1 g of 80% sodium hydride in paraffin oil to obtain the base free. After two hours, the solution is filtered through kieselguhr to separate the. NaCl and added dropwise to a solution of 3-trimethylsilyloxy-2-propenylidene-1-piperidinium chloride in 20 ml of carbon tetrachloride
(prepared from 5.6 g of 3-piperidino-acrolein and 4.3 g of trimethylchlorosilane). After two hours of stirring at room temperature,

  
the solution is concentrated under vacuum until the hydrochloride crystallizes.

  
 <EMI ID = 264.1>

  
the salt is filtered off and washed with cold dimethylsulfoxide and ether. Yield after vacuum drying: 7.6 g (52.8%); Pf. 192 [deg.].

  
From this compound, by reaction with a solution of carbonate de.so-

  
 <EMI ID = 265.1>

Example 21

  
10.0 g of 4-phenyl-1-hydrazino-phthalazine hydrochloride are dissolved in

  
 <EMI ID = 266.1>

  
free by 1.5 g of 80% sodium hydride in paraffin oil, which causes partial crystallization. To this suspension is added dropwise with stirring at 20 [deg.] The / 3-methoxy-2propenylidene- (1) 7-piperidinium methoxysulfonate prepared from 5.6 g of 3-piperidinoacolein and 10 g of dimethyl sulfate in 20ml of dimethoxyethane. After 2 hours of stirring, the solution is concentrated under vacuum to dryness, the residue is taken up in ethyl acetate and filtered off by suction. The filtration residue is dissolved in chloroform, extracted with an ammonia solution cooled with ice, the chloroform phase is separated, washed to neutrality with water and dried over calcined potassium carbonate. By adding an excess of a solution

  
 <EMI ID = 267.1>

  
double drate. Yield: 34.7% of theory; Pf. 159-160 [deg.].

Example 22

  
Analogously to Example 21, 1-hydrazino-phthalazine hydrochloride was prepared by reacting with / T3-methoxy- methoxysulfonate.

  
 <EMI ID = 268.1>

  
ridino-propenylidene) -hydrazino7-phthalazine. Yield: 72.6% of theory; Pf. 2230.

Example 23

  
Analogously to Example 21, the reaction of 4-

  
 <EMI ID = 269.1>

  
Yield: 49.4% of theory; Pf. 240 [deg.].

Example 24

  
 <EMI ID = 270.1>

  
hydrazinoT-phthalazine and 2- (2-furylmethylamino) -4-chloro-5sulfamyl-benzoic acid is filtered off with suction, suspended in 500ml of ice-water, centrifuged, washed with aqueous methanol and dried at 60 [ deg.] under vacuum. Yield: 97.4% of theory; Pf. 148-149 [deg.].

Example 25

  
 <EMI ID = 271.1> <EMI ID = 272.1>

  
20 ml of chloroform and prepared from 2.5 g of 3-dimethylaminoacolein and 3.2 g of dimethyl sulfate. After stirring for a further two hours the reaction is complete and the methoxysulfonate

  
 <EMI ID = 273.1>

  
zine crystallizes. Complete precipitation is produced by adding ether, filtering off with suction and washing with benzene.

  
The product is dissolved in ice water, the base is liberated by adding concentrated ammonia and extracted with ether. The ethereal extract is dried over sodium carbonate and concentrated to approximately 50 ml. By adding hydrochloric acid dissolved in ether, the product is precipitated in the form of the hydrochloride, filtered by suction and washed with ethyl acetate. 7.8 g of 1- hydrochloride are obtained.

  
 <EMI ID = 274.1>

  
zine of Pf. 213 [deg.] .. -

  
By reaction of the corresponding hydrazinoazaheterocycles, the following compounds were prepared in an analogous manner:

  
 <EMI ID = 275.1>

  
lidene) -hydrazino7-pyridazine (yield: 19% of theory; Pf. 162 [deg.]
(with decomp.));

  
 <EMI ID = 276.1> <EMI ID = 277.1>

  
hydrazino7-phthalazine (yield 35.1% of theory, Pf. 237-2400
(decomp.));

  
 <EMI ID = 278.1>

Example 26

  
To a solution of 1.7 g (16.6 mmol) of 3-dimethylaminopropenal in 10 ml of anhydrous dichloromethane in the absence of moisture and with external cooling with ice-water, is added dropwise 1.8 (16.6 mmol) of

  
 <EMI ID = 279.1>

  
 <EMI ID = 280.1>

  
about 1 hour a crystalline precipitate. After standing overnight, the reaction mixture is diluted with ether to double the volume and filtered by suction. The resulting filter cake is dried under vacuum.

  
 <EMI ID = 281.1>

  
 <EMI ID = 282.1>

Example 27

  
100 g of 1-hydrazinophthalazine hydrochloride are suspended in
200 ml of methanol, brought into contact, under external cooling with ice-cold water, with 30 g of 3-dimethylaminopropenal and stirred at room temperature until complete reaction (approximately 6 to 8 hours). This causes the suspension initially colored orange yellow to transform into a dark red crystalline mass of very fine needles. The mixture is diluted with ice water 1:10, the crystalline mass is filtered off by suction and the filter cake is washed several times with water <EMI ID = 283.1>

  
74.0 g (74% of theory) of 3- / phthalazinyl hydrochloride are obtained.

  
 <EMI ID = 284.1>

Example 28

  
Analogously to Example 27, 3-piperidinoacolein is prepared by reacting with 4-chloro-1-hydrazinophthalazine methanesulfonate in

  
 <EMI ID = 285.1>

  
 <EMI ID = 286.1>

Example 29

  
Analogously to Example 27, 3-dimethylaminopropenal is prepared by reacting with 4-methyl-1-hydrazinophthalazine hydrochloride in

  
 <EMI ID = 287.1>

  
39.2% of theory; Pf. 161-162 [deg.] ..

Example 31

  
 <EMI ID = 288.1>

  
 <EMI ID = 289.1>

  
overnight, the mixture is introduced with stirring into 500 ml of ice-water, the precipitate is filtered off with suction and the filter cake is washed several times with aqueous methanol (1: 1). The product is dried under <EMI ID = 290.1> <EMI ID = 291.1>

Example 32

  
Analogously to Example 31, a reaction of hydrochloride is obtained.

  
 <EMI ID = 292.1>

  
the theory; Pf. 150 [deg.].

Example 33

  
Analogously to Example 31, a hydrochloride reaction is obtained

  
 <EMI ID = 293.1>

  
 <EMI ID = 294.1>

Example 34

  
 <EMI ID = 295.1>

  
methanol, 0.7 g of methanesulfonic acid is added dropwise with stirring. and then 0.7 g of 3-dimethylaminopropenal. The reaction mixture is stirred for a further 6 hours at room temperature, then the yellow-orange crystal mass is filtered off with suction and washed several times with methanol and water. After drying

  
 <EMI ID = 296.1>

  
 <EMI ID = 297.1>

Example 35

  
 <EMI ID = 298.1>

  
additionally, the mixture is concentrated under vacuum to dryness to release

  
 <EMI ID = 299.1> <EMI ID = 300.1>

  
Methylene chloride are dried over sodium sulfate and concentrated in vacuo. The red oil obtained is taken up in a little absolute ethanol and converted into the hydrochloride with a solution of hydrochloric acid in ether, which, after precipitation by addition of ether, is again dissolved in a little ethanol. and recrystallized by adding ethyl acetate. In this way, 2.4 g (19.5% of theory) of

  
 <EMI ID = 301.1>

  
ZinoT-propene of Pf. 98 [deg.] (decomp.).

Example 36

  
 <EMI ID = 302.1>

  
 <EMI ID = 303.1>

Example 37

  
 <EMI ID = 304.1>

  
(prepared according to Example 2) are dissolved in methylene chloride

  
and undergo fractional crystallization, which produces 3 different fractions differentiated by their melting point and orange tone.

  
 <EMI ID = 305.1>

  
indicate that they are syn / anti isomers and mixtures thereof.

  
The appended table appearing on page 52 gives a synoptic indication of the yield, the melting point, the syn / anti isomer ratio and the chemical shift of the methane protons in ppm as well as the solvent (Sv) used for each of the NMR measurements.

  
With regard to the structure of isomers, reference is made

  
to K. Feldmamet al., Z. Naturforschung 22 b (1967), 7,722-31 (cis / trans-

  
 <EMI ID = 306.1>

  
 <EMI ID = 307.1>

  
Georg Thieme Verlag Stuttgart 1967 (syn / anti-Konfiguration).

Example 38

  
Preparation of tablets

  
The tablets contain the following constituents in the proportions indicated: <EMI ID = 308.1>
 <EMI ID = 309.1>
 
 <EMI ID = 310.1>
 Components 1, 2 and 3 with 4 are moistened with about 20 liters of water and granulated in a sieve of 1.25 mm mesh width. The granulate is dried in a fluid bed dryer to a relative humidity of 50 to 60% and then components 5, 6 and 7. The finished granulate is pelletized to obtain tablets of 200 mg and 8 mm in diameter. .

Example 39-

  
Preparation for 100 liters (ampoules)

  
 <EMI ID = 311.1>

  

 <EMI ID = 312.1>


  
Component 1 is dissolved in about 80 liters of water and then Component 2. The solution is adjusted to a pH of '7.0%. 0.5 and the remaining water is added. The solution is sterile filtered and placed under aseptic conditions in 2 ml ampoules.

  
 <EMI ID = 313.1>

  
Preparation for tablets.

  

 <EMI ID = 314.1>


  
 <EMI ID = 315.1>

  
Component and 30 kg of component 3 are added to this mixture, and

  
as well as the rest of components 4, 5 and 6 and sieved. The mixture is moistened with a solution of component 7 and 8 in 35 liters of water and strained through a sieve with a mesh width of 1.25 mm. After drying,

  
 <EMI ID = 316.1>

  
 <EMI ID = 317.1>

  
 <EMI ID = 318.1>

  
and pelletized to obtain tablets of 200 mg and 8 mm in diameter.

Example 41 -

  
Preparation for tablets

  

 <EMI ID = 319.1>


  
Components 1, 2, 3 and 4 are mixed and moistened with component

  
 <EMI ID = 320.1>

  
in an oven at 50 [deg.] and finally passed through a sieve. The granulate is dried to a relative humidity of 45-50% and after addition of components 6, 7 and 8 and careful mixing, pelletized to obtain tablets of 200 mg in weight and 8 mm in diameter.

  
 <EMI ID = 321.1>

  
Preparation for tablets .... -
 <EMI ID = 322.1>
- Components 1, 2 and 3 with 4 are moistened by about 20 liters <EMI ID = 323.1>

  
aggregate is dried in a fluidized bed dryer to humidity

  
 <EMI ID = 324.1>

  
The final granulate is a pellet to obtain 100 mg tablets.

  
 <EMI ID = 325.1>

  
Preparation for 100 liters (ampoules).

  
 <EMI ID = 326.1>

  

 <EMI ID = 327.1>
 

  

 <EMI ID = 328.1>


  
Component 1 is dissolved in about 80 liters of water and then Component 2. The solution is adjusted to a pH of 7.0. 0.5 and the remaining water is added. The solution is sterile filtered and placed under aseptic conditions in 2 ml ampoules.

Example 44

  
Preparation for tablets

  
 <EMI ID = 329.1>

  

 <EMI ID = 330.1>


  
Component 2 is mixed with 5 kg of component 4 and finely ground. Component 1 and 30 kg of component 3 are added to this mixture, together with the remainder of components 4, 5 and 6 and sieved. The mixture is moistened with a solution of constituents 2 and 8 in 35 liters of water and strained through a sieve of 1.25 mm mesh width. After drying, the

  
 <EMI ID = 331.1>

  
pelletized to obtain tablets of 200 mg.

  
 <EMI ID = 332.1>

  
Preparation for tablets

  

 <EMI ID = 333.1>


  
Components 1, 2, 3 and 4 are mixed and one. moistened with: component 5 (dissolved in <1> 5 liters of water) and granulated. Then we pre-dried

  
in an oven at 50 [deg.] and finally passed through a sieve. The granulate is dried to a relative humidity of 45 to 50% and after addition of components 6, 7 and 8 and careful mixing, it is pelletized to obtain

  
 <EMI ID = 334.1>
 <EMI ID = 335.1>
 <EMI ID = 336.1>
  <EMI ID = 337.1>

CLAIMS

  
1. Vinylogue amidrazones of the general formula I

  

 <EMI ID = 338.1>


  
in which :

  
B represents the group

  

 <EMI ID = 339.1>


  
R represents a .substituent; any other than hydrogen or a part

  
of a condensed ring,

  
 <EMI ID = 340.1>

  
a lower alkyl group, an optionally substituted phenyl group or together represent an alkylene group optionally

  
substituted,

  
 <EMI ID = 341.1>

  
aliphatic or alicyclic goodness, optionally substituted, a

  
optionally substituted phenyl or phenalkyl group or together represent an alkylene bridge optionally interrupted by an <EMI ID = 342.1>

  
their addition salts with. the. cis / trans and syn / anti acids and isomers.


    

Claims (1)

2. Vinylogue amidrazones according to claim 1 of the formula <EMI ID = 343.1> <EMI ID = 344.1> <EMI ID = 345.1> B represents the groups <EMI ID = 346.1> <EMI ID = 347.1> ) this represents a hydrogen atom, a halogen atom, an alkyl group lower or an optionally substituted phenyl group, R and R are the same or different and represent a hydro- atom .gene, a lower alkyl group, a phenyl group optionally substituted in the para position by chlorine or together form a propylene group optionally substituted centrally by a lower alkyl, preferably methyl, <EMI ID = 348.1> R and R are the same or different and represent a hydro group saturated or unsaturated aliphatic carbon, optionally substituted in the terminal position by a lower alkoxy group or a lower dialkylamino group, an alicyclic hydrocarbon group comprising from 5 to 6 carbon atoms, a phenyl group <EMI ID = 349.1> alkyl residue, optionally substituted in the para position by chlorine, lower alkyl or lower alkoxy or together form <EMI ID = 350.1> <EMI ID = 351.1> smells of a lower alkyl group, <EMI ID = 352.1> <EMI ID = 353.1> lower amino or lower dialkylamino, <EMI ID = 354.1> <EMI ID = 355.1> lower alkyl, a lower alkoxy group, an optionally substituted phenyl or phenoxy group, R represents a hydrogen atom, a lower alkyl group or <EMI ID = 356.1> <EMI ID = 357.1> R represents a hydrogen atom, a lower alkyl group or phenyl, s represents a number from 0 to 7, their addition salts with cis / trans and syn / anti acids and isomers. 3. Vinylogue amidrazones according to claim 1 of the formula <EMI ID = 358.1> <EMI ID = 359.1> in which <EMI ID = 360.1> <EMI ID = 361.1> <EMI ID = 362.1> lower alkyl group, or a phenyl group optionally substituted in the para position by chlorine, lower alkyl or lower alkoxy, <EMI ID = 363.1> <EMI ID = 364.1> R and R represent a hydrogen atom, R and R each represent a methyl group or together form a <EMI ID = 365.1> <EMI ID = 366.1> <EMI ID = 367.1> lower alkoxy or a phenyl residue, <EMI ID = 368.1> their addition salts with and isomers, cis / trans and syn / anti. <EMI ID = 369.1> <EMI ID = 370.1> <EMI ID = 371.1> <EMI ID = 372.1> <EMI ID = 373.1> <EMI ID = 374.1> in which X represents a hydrogen atom, a halogen atom, a lower alkyl group or a phenyl group optionally <EMI ID = 375.1> or lower alkoxy, R and R are the same or different and represent a hydrogen atom. <EMI ID = 376.1> optionally substituted in the para position by chlorine or . together form a propylene group possibly substituted <EMI ID = 377.1> <EMI ID = 378.1> <EMI ID = 379.1> saturated or unsaturated aliphatic hydrocarbon, optionally substituted in the terminal position by a lower alkoxy group or a lower dialkylamino group, an alicyclic hydrocarbon group comprising from 5 to 6 carbon atoms, a phenyl or phenalkyl group comprising from 1 to 2 carbon atoms in the alkyl residue, optionally substituted in the para position by chlorine, lower alkyl or lower alkoxy or together form a group <EMI ID = 380.1> represents a lower alkyl group, their addition salts with cis / trans and syn / anti acids and isomers. 6. Vinylogue amidrazones according to claim 1 of the general formula I -. <EMI ID = 381.1> <EMI ID = 382.1> <EMI ID = 383.1> a phenyl group, <EMI ID = 384.1> R. and R represents a hydrogen atom, 3 &#65533; . <EMI ID = 385.1> <EMI ID = 386.1> 7. Compounds according to claim 6, characterized in that X represents a hydrogen atom or in particular a chlorine atom. <EMI ID = 387.1> cis / trans and syn / anti ... '' <EMI ID = 388.1> 16. Medicaments characterized in that they contain amino acids <EMI ID = 389.1> <EMI ID = 390.1> general formula I according to claim 1, characterized in that an oximinium salt of general formula IV is reacted <EMI ID = 391.1> <EMI ID = 392.1> <EMI ID = 393.1> <EMI ID = 394.1> <EMI ID = 395.1> <EMI ID = 396.1> azaheterocycle of formula II <EMI ID = 397.1> in which B represents the group <EMI ID = 398.1> R represents any substituent other than hydrogen or a part a condensed ring, and that the salt obtained is optionally subsequently converted into a base <EMI ID = 399.1> free and / or in an addition salt with a pharmacologically acceptable acid. 18- The method of claim 17, characterized in that reacts an oximinium salt of -general formula IV produced in situ with the hydrazinoazaheterocycles compounds (II). 19. Symmetric and asymmetric vinylogous hydrazidines of the general formula XIa or XIb <EMI ID = 400.1> in which E and F are the same or different and represent unsaturated azaheterocycles with one or more rings which with incorpora- -tion of hydrazino groups, form an amidrazone system of the partial structure G <EMI ID = 401.1> 20 where R represents any other substituent. as hydrogen or part of a condensed ring, as well as their cis / trans or syn / anti isomers, their tautomers and their addition salts with acids. 20. Symmetric or asymmetric hydrazidines according to the claim. <EMI ID = 402.1> <EMI ID = 403.1> <EMI ID = 404.1> <EMI ID = 405.1> <EMI ID = 406.1> <EMI ID = 407.1> wherein <EMI ID = 408.1> lower alkylamino or lower dialkylamino, <EMI ID = 409.1> or a piperidino group,. <EMI ID = 410.1> lower alkyl or a phenyl group optionally substituted in <EMI ID = 411.1> <EMI ID = 412.1> <EMI ID = 413.1> represents a lower alkyl or lower alkoxy group, or an optionally substituted phenyl or phenoxy group and t represents <EMI ID = 414.1> <EMI ID = 415.1> <EMI ID = 416.1> <EMI ID = 417.1> <EMI ID = 418.1> <EMI ID = 419.1> <EMI ID = 420.1> <EMI ID = 421.1> <EMI ID = 422.1> <EMI ID = 423.1> <EMI ID = 424.1> wherein <EMI ID = 425.1> <EMI ID = 426.1> <EMI ID = 427.1> R represents a hydrogen atom, a chlorine atom or a group <EMI ID = 428.1> R represents a lower alkyl group and <EMI ID = 429.1> as well as their isomers, their tautomers and their addition salts with acids. 22. Hydrazidines according to claim 19'-. characterized in that <EMI ID = 430.1> <EMI ID = 431.1> in which <EMI ID = 432.1> as well as their isomers, their tautomers or their addition salts with <EMI ID = 433.1> <EMI ID = 434.1> propene, its isomers, tautomers and its additives with acids. 25. Medicines characterized in that they contain hydra- <EMI ID = 435.1> 26. Process for the preparation of vinylogue hydrazidines of the general formula XI according to claim 19, characterized in that <EMI ID = 436.1> a) a hydrazinoazaheterocycle of the general formula XII <EMI ID = 437.1> in which E represents the group <EMI ID = 438.1> <EMI ID = 439.1> and R represents any substituent other than hydrogen or a part of a condensed ring, with a 3-aminopropenal of formula XIII <EMI ID = 440.1> in which <EMI ID = 441.1> optionally substituted aliphatic or alicyclic carbon, an optionally substituted phenyl or phenalkyl group or together form an alkylene bridge optionally interrupted by a heteroatom, and optionally then transforms in a conventional manner the free base obtained into its addition salt with pharmacologically admissible acids or vice versa, ' or . b) in that a hydrazinoazaheterocycle of the general formula is reacted <EMI ID = 442.1> <EMI ID = 443.1> in which F represents the group <EMI ID = 444.1> R represents any substituent other than hydrogen or part of a condensed ring, <EMI ID = 445.1> <EMI ID = 446.1> <EMI ID = 447.1> and that optionally then converts in a conventional manner the free base obtained into its addition salt with the pharmacologically admissible acids or vice versa. 27. A method according to claim 26, characterized in: that one of the compounds involved in the reaction is used in the form of an addition salt with acids. <EMI ID = 448.1> 28. Process according to Claims 26 and 27, characterized in that the hydrazinoheterocycle is used in the form of an addition salt with acids.