DE1239292B - Process for the preparation of guanylhydrazones of araliphatic carbonyl compounds - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

C07d

German class: 12 ο -17/04

Number:
File number:
Registration date:
Display day;

1239292
F42767IVb / 12o
April 30, 1964
April 27, 1967

From 4en German patents 943 408, 958 832 and 963 513 are processes for the production of Guanylhydrazones of aliphatic, aromatic and aromatic-heterocyclic aldehydes or ketones known. These compounds are useful in combating bacterial infections.

The invention relates to a process for the preparation of guanylhydrazones of araliphatic carbonyl compounds or their salts with non-toxic acids, which is characterized in that one compounds with more than one aldehyde or ketocarbonyl group in which two carbonyl groups are separated from each other by an aromatic ring and 3 or more carbon atoms, in a manner known per se either

a) with aminoguanidines of the general formula H ₂ NNC-NHB

Process for the production of
Guanylhydrazones more araliphatic
Carbonyl compounds

Applicant:

Paint factories Bayer Aktiengesellschaft,

Leverkusen

Named as inventor:

Dr. Siegismund Schütz,

Dr. Karlheinz Meyer, Wuppertal-Elberfeld;

Dr. Kurt Stoepel, Wuppertal-Vohwinkel;

Dr. Hans-Günther Kroneberg,

Wuppertal-Elberfeld

E NA

or reacts their salts or b) with thiosemicarbazides of the general formula

H ₂ NNC-NH-B

condensed and the condensation products either directly or after their conversion into S-alkylisotbiosemicarbazones with amines of the general formula

H ₂ NA

implements or

c) with S-alkylisothiosemicarbazides of the general formula

H ₂ NNC = NA

E S - alkyl

condensed and the products obtained with amines of the general formula

H ₂ NB

implements or

d) with hydrazines of the general formula

HiN-NH

E.
condensed and the hydrazones obtained with cyanamides of the general formula

N = C-NH-B

or S-alkylisothioureas in general formula

N / A

;.
Alkyl - S - C - NHB

implements

and the guanylhydrazones obtained are isolated as such or in the form of their salts with non-toxic acids.

In the formulas given above, A stands

and E represents hydrogen or a branched or unbranched aliphatic or an alicyclic Remainder with 1 to 6 carbon atoms each, which can carry one or more hydroxyl groups. B means Hydrogen, an unsubstituted or substituted by one or more hydroxyl groups alicyclic or branched or unbranched aliphatic radical with 1 to 6 carbon atoms each, this radical also, optionally via a nitrogen, oxygen or sulfur atom, with A may be linked, a nitro or an amino group or a basic radical D. D stands for a Remainder of the general formula

, R

709 577/362

in which «= 0 to 8 and / 1 or 2 and R and R ¹ each represent hydrogen, for identical or different, unsubstituted, alicyclic or branched or unbranched aliphatic radicals each with up to 6 carbon atoms, which, if appropriate, can also be connected to one another via a nitrogen, sulfur or oxygen atom.

The chains fused to the aromatic ring, which can also be a heterocycle, the carbonyl groups of which are converted into the guanylhydrazone groups, can be of any length, saturated or unsaturated, branched or unbranched, by nitrogen, oxygen and / or sulfur atoms as well alicyclic, aromatic or heterocyclic rings and substituted by OH, O-acyl, O-alkyl, O-alkenyl, O-alkynyl, carboxyl, halogen, CN, NRR ¹ , cycloalkyl, aryl, aralkyl and heterocycles.

The aromatic ring can be substituted by halogen, alkyl, NRR ¹ , NO ₂ , OH, O - acyl, O - · alkyl, O - alkenyl, cycloalkyl, CN, SO ₂ R, carbonyl, carbonamide, heterocycles and alicyclics and / or have fused alicyclic and heterocyclic non-aromatic rings. as

Suitable starting materials for the process according to the invention are, for. B. l, 4-bis - (/ 3-acetyl-ethyl) benzene, 1,3 - bis - (ß - acetyl - ethyl) - benzene, 1,4 - bis (ß - acetyl - vinyl) - benzene , 1,3 - bis (ß - acetyl - vinyl) benzene, 4- (ß - benzoyl - vinyl) - benzaldehyde, 1,4 - bis (ß - benzoyl - ethyl) - benzene, 1,4 - bis - (ß - benzoylpropyl) - benzene, 1,4 - bis - (ß - ρ - toluyl - ethyl) - benzene, 1,4 - bis - (ß - benzoyl - vinyl) - benzene, 1,4 - bis ( ß - benzoyl - propenyl) - benzene, 1,4 - bis - (ß - ρ - toluyl - vinyl) - benzene, ß, ß ' - ρ - phenylene - diacrolein, 1,1' - ρ - phenylene - di - [ pentadiene - (1,3) - al - (5)], 1,2 - phenylene - diacet - aldehyde, 2,5 - furan - β, β ' - dipropion - aldehyde, 2,5 - bis - (ß - acetyl - ethyl) - thiophene, 4,4 '- (p - phenylene) - bis - [4 - methyl - 2 - pentanone].

The guanylhydrazones which can be prepared according to the invention act similarly to cardiac glycosides, i.e. i.e., they increase the force of contraction of the heart muscles. Similar acting synthetically producible compounds are not yet known.

The products of the process can be used as such or in the form of their salts with non-toxic organic substances or inorganic acids. Suitable acids are e.g. B. acetic acid, propionic acid, lactic acid, Maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, salicylic acid, naphthalene-l, 5-disulfonic acid, Phosphoric acid, hydrochloric acid.

The products of the method according to the invention have a positive inotropic cardiac muscle effect, which is proven by the following pharmacological test arrangements:

1. Isolated spontaneously beating atrial preparation of the guinea pig. Method see P-Holtz and E. Westermann, Naunyn-Schnuede-, bergs Arch. exp. Path. and Pharmak., 225, p. 421 (1955), as well as G. K rο η e b e r g and K. S tο epel, Naunyn-Schmiedebergs Arch. Exp. Path.

Γι Pharmak
u. rnarmaK.,

2. Isolated frog heart according to Sträub. method s. H. F r ü h η e r, detection and determination of poisons on biol. Paths, Urban and Schwarzenberg, Berlin-Vienna (1911), pp. 123 to 129.

3. Inhibition of the transport ATPase of the guinea pig heart (K. R e ρ ke and HJ P ο rt ius, Experientia, 19, p. 452 [1963]).
Obtaining the transport ATPase according to T. Kο η ο and SP Collowick, Arch. Biochem. Biophys., 93, pp. 520-533 (1961). Determination of the enzyme activity according to JV Auditore, Proc. Soc. exp. Biol. Med., 110, pp. 595-597 (1962).

Investigation results
Bisguanyl hydrazone dihydrochloride
^des W-Bis - ^ - acetylvmyO-benzene

Toxicity, mouse

12.0 to 16.0 mg / kg i.p. v.

Atrium, guinea pigs

Positive inotropic effect from concentrations of 3 · 10 ~ ^e g / ml. Cardiac muscle contracture and arrest at concentrations of 3 x 10 ~ ^B g / ml.

Frog heart

Positive inotropic effects and systolic cardiac arrest from concentrations of 10- ^ g / ml.

Transport ATPase, guinea pig

At concentrations of 10 ~ ⁵ molar = 23% inhibition.

Bisguanyl hydrazone dihydrochloride

^of M- P-phenylendmcrolem
Toxicity, mouse

10.0 to 12.5 mg / kg iv
Atrium, guinea pigs

Positive inotropic effect from concentrations of 3 · 10 ~ ⁵ g / ml. Heart muscle contracture from concentrations of 10 ~ ⁵ g / ml.
Frog heart

Positive inotropic effects and systolic cardiac arrest from concentrations of 0.5 · 10 ~ ⁴ g / ml. The following examples illustrate the invention.

example 1

4 g of 1,4 - bis - [ß - (p - chloro - benzoyl) - vinyl] - benzene are dissolved in 600 ml of chloroform, diluted with 300 ml of ethanol and, after adding a solution of 3 g of aminoguanidine hydrogen carbonate in methanolic hydrochloric acid ( pH value = 2) Stored for 3 days under nitrogen at room temperature. It is concentrated in vacuo to 150 ml, the solution is stirred into ether, the flakes which precipitate are filtered off with suction and boiled with a little ethanol.

To give 3 g of the dihydrochloride 1.4 -. Bis [/ 3- (p-chloro-benzoyl) -vinyl] -benzolbisguanylhydrazons, mp 256 to 26O ⁰ C (decomposition).

The following is prepared analogously: dihydrochloride of 1,4-bis- (| S-acetyl-vinyl) -benzolbisguanylhydrazone, Mp. 320 ° C (decomposition).

Example 2

₂ i ^ ßis-OS-acetyl-äthyO-benzene are in 100 ml of f ^{hano1 8} ^ - ™ a solution of 2 5 g

Aminoguanidine hydrogen carbonate mixed with methane hydrochloric acid with a pH of 2. The mixture is left to stand for 3 days ^{under solid material at} _{room temperature, the precipitate is filtered off with suction in ether and} recrystallized from alcohol.

2 g of dihydrochloride of 1,4-bis (^ - acetylethyl) -benzolbisguanylhydrazone are obtained, Mp 198 to 200 ° C (decomposition).

Example 3

3.7 g of jS.jS'-p-phenylenediacrolein are dissolved in methanol dissolved and treated with a solution of 6 g of aminoguanidine hydrogen carbonate in methanolic hydrochloric acid and stirred at room temperature (pH = 3) until the reaction has ended. Afterward if one precipitates by introducing it into ether, the precipitate which separates out is separated off and treated with it Acetone and precipitates from methanol-ether.

This gives 4.5 g of the dihydrochloride ß / S'-p-phenylene-diacroleinbisguanylhydrazonsvomSchmelzpunkt 249 to 25O ⁰ C.

In an analogous manner, dihydrochloride of 1,1 '- ρ - phenylene - bis - [pentadiene - (1,3 - al - (5) - bisguanylhydrazones], melting point> 360 ° C; tetrahydrochloride of β, ß' - ρ is obtained - Phenylene - diacroleinbis - [1 - (ß - diethylamino-ethyl) -guanylhydrazone], mp 170 to 175 ° C.

Example 4

7 g of aminoguanidine hydrogen carbonate are dissolved in methanolic hydrochloric acid to pH = 2, mixed with a solution of 5 g of 2,5-bis (/? - acetylethyl) -furan in 10 ml of ethanol and added for 3 days under N ₂ Stored at room temperature. The mixture is stirred into ether and decanted, the viscous residue is boiled up with a little ethanol, the crystals formed are filtered off with suction and recrystallized from ethanol.

This gives 6 g of the dihydrochloride of 2,5-bis -. [(/ S-acetyläthyl) -furan-guanylhydrazons], mp 100 ⁰ C.

Example 5

Analogously to Example 4, starting from 2,5- bis- (β -acetyl-ethyl) -pyrrole, the dihydrochloride of 2,5-bis- [(/ 5-acetyl-ethyl) -pyrrole-guanylhydrazone], mp. 152 ° C (decomposition).

Claims (1)

Claim: Process for the preparation of guanylhydrazones of araliphatic carbonyl compounds or their Salts with non-toxic acids, thereby characterized in that compounds with more than one aldehyde or ketocarbonyl group, in which two carbonyl groups through an aromatic ring and 3 or more carbon atoms are separated from each other, either in a manner known per se a) only aminoguanidines of the general formula H ₂ NNC-NHB E NA or converts their salts or b) with thiosemicarbazides of the general formula H ₂ NNC-NH-B i
IT condensed and the condensation products either directly or after their conversion in S-alkylisothiosemicarbazones with amines 60 of the general formula H ₂ NA
implements or c) with S-alkylisothiosemicarbazides of the general formula H ₂ NNC = NA E S-alkyl condensed and the products obtained with amines of the general formula H ₂ NB implements or d) with hydrazines of the general formula H ₂ N-NH condensed and the hydrazones obtained with cyanamides of the general formula N = C-NH-B or S-alkylisothioureas of the general formula N / A Alkyl-S-C-NHB implements and the guanylhydrazones obtained as such or in the form of their salts with non-toxic acids isolated, where in the above formulas A and E represent hydrogen or a branched or unbranched aliphatic or an alicyclic radical each having 1 to 6 carbon atoms, which can carry one or more hydroxyl groups, are and B is hydrogen, one unsubstituted or with one or more Hydroxyl substituted alicyclic or branched or unbranched aliphatic Remainder each with 1 to 6 carbon atoms, this remainder also, optionally via a nitrogen, Oxygen or sulfur atom, can be connected to A, a nitro or an amino group or a basic radical D, where D is a radical of the general formula -CH ■ (3- /) R ¹ in which η = 0 to 8 and / 1 or 2 and R and R ¹ each represent hydrogen, identical or different, unsubstituted or alicyclic or branched or unbranched aliphatic radicals each with up to to 6 carbon atoms, which, optionally also via a nitrogen, sulfur or oxygen atom, can be connected to one another. 709 577/362 4.67 © Bundesdruckerei Berlin