DE1239291B - Process for the preparation of guanyl hydrazone of aromatic polycyclic carbonyl compounds - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

C07c

C07d

German KL: 12 ο -17/04

Number: 1 239 291

File number: F 42610IV b / 12 ο

Filing date: April 15, 1964

Open date: April 27, 1967

It is known that guanylhydrazones of polycyclic Ketones that contain aromatic rings have a bacteriostatic or bactericidal effect (German patent specification 942 627, USA patent specification 2 865 961 and Zh. Oshch. Khim., 32 [1962], p. 1077) to have. Bis-guanylhydrazones of diphenyl-diketones and diphenyl-dialdehydes (German Patent 943 408) and monoguanyl hydrazones of polycycic aromatic ketones (Anales asoc. Argentina, 22 [1934], p. 41).

The invention relates to a process for the preparation of guanylhydrazones of aromatic polycyclic Carbonyl compounds or their salts with non-toxic acids, which is characterized by that you have polycyclic aromatic compounds that have more than one keto or aldehyde carbonyl group included, either in a manner known per se

a) with aminoguanidines of the general formula

H ₂ N - N - C - NHB

E NA
or converts their salts or

b) with thiosemicarbazides of the general formula

H ₂ N-N-C-NH-B

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

H ₂ NA

implements or

Process for the preparation of guanylhydrazones of aromatic polycyclic
Carbonyl compounds

Applicant:

Paint factories Bayer Aktiengesellschaft,

Leverkusen

Named as inventor:

Dr. Siegismund Schütz,

Dr. Karlheinz Meyer,

Dr. Werner Meiser, Wuppertal-Elberfeld;

Dr. Kurt Stoepel, Wuppertal-Vohwinkel;

Dr. Hans-Günther Kroneberg,

Wuppertal-Elberfeld

d) with hydrazines of the general form]
H ₂ N - NH

condensed and the hydrazones obtained with cyanamides of the general formula

Ne = C-NH-B

or S-alkylisothioureas in general formula

N / A

Alkyl-S-C-NHB

implements

c) with S-alkylisothiosemicarbazides of the general 40 and the resulting guanylhydrazones as such or Formula isolated in the form of its salts with non-toxic acids.

In the formulas given above, A and E represent hydrogen or a branched or unbranched aliphatic or an alicyclic

E S - alkyl 45 radical with 1 to 6 carbon atoms each, the one

or can carry several hydroxyl groups; B means hydrogen, an unsubstituted or with one or more hydroxyl groups substituted alicyclic or branched or un-

H ₉ N-N-C = NA

condensed and the products obtained with amines of the general formula

H ₂ NB

implements or

branched aliphatic radical each having 1 to carbon atoms, this radical also, optionally via a nitrogen, oxygen or

709 577/361

Sulfur atom, can be connected to A, a nitro or an amino group or a basic radical D. D stands for a radical of the general formula

(CH ₂ ) "- N:

R.
R ¹

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

Polycyclic aromatic compounds here are compounds with two or more aromatic compounds To understand rings, which can also contain N, S or O as heteroatoms in the skeleton. Here must two aromatic rings through two bonds, optionally via N, S, C or O as bridge atoms be linked to each other.

The aromatic system can be substituted by further aromatic rings. These polycyclic compounds can also be substituted in any position by OH, O — alkyl, O-acyl, NRR ¹ , halogen, alkyl, alkenyl, alkynyl, cycloalkyl, NO ₂ , CN, carboxyl, carbonamide, SO ₂ R or sulfonamide.

Suitable starting materials are ζ. Β. Naphthalene-1,8-dialdehyde, naphthalene-2,7-dialdehyde, 2-acetylnaphthaldehyde, 1,5-diacetylnaphthalene,

1,8- diacetylnaphthalene, 1,4- dibenzoylnaphthalene, 1,5 - dibenzoylnaphthalene, 1,6 - dibenzoylnaphthalene, 2,6-dibenzoylnaphthalene, 2,6-dimethyl-1,5-dibenzoylnaphthalene, 1 - (o - Benzoylbenzoyl) - naphthalene, 6 - (o - Formylphenyl) -1 - naphthaldehyde, 4 - hydroxy-1, 3 - dipropionylnaphthalene, 4,8 - dihydroxy -1,5 - dibenzoylnaphthalene, 1,4,5,8-tetrabenzoylnaphthalene, 2-acetylfluorenone, 2-propionylfluorenone, 1-benzoylfluorenone, 4-BenzoyIfluorenone, 2,7-Diacetylfluorenone, 2,7-dibenzoylfluorenone, biacendione, 5,5'-diacetylbiacendione, 5,5'-dibenzoylbiacendione, 9,10-dibenzoylanthracene, 10-benzoylanthrone, 3- (10-anthronyl) indan-1-one, 10-hydroxy-1,5 - bis - (2,4-dimethylbenzoyl) - anthrone, 1,3-dibenzoylanthracene, 2,6-dibenzoylanthracene, Bianthrone, 3,3'-dihydroxybianthrone, 9,10-bis (« - phenylacetonylidene) - 9.10 - dihydroretene, 9.10 - dihydroxy - 9.10 - diacetonyl - 9.10 - dihydrophenanthrene, 1,5 - diacetylanthraquinone, 1,8 - diacetylanthraquinone, 2,8-chrysoquinone, 1,6-dibenzoylpyrene, 3,8-dibenzoylpyrene, Pyrene-3,8-quinone, pyrene-3,10-quinone, benzanthrone-2-aldehyde, 6-benzoylbenzanthrone, pentacene-5,12-quinone, 3,4-benzopyrene-5,10-quinone, perylene-3,10-quinone, I, II-dimethyl-perylene-S.lO-quinone.

Analogous derivatives of quinoline, isoquinoline, carbazole, acridine, phenanthridine, 1,2-benzodiazines, quinazolines, quinoxalines, phenazines, phenazons, phenanthrolines, thioxanthens, Thiosanthone, phenoxazine, phenothiazine, diphenyl sulfone, diphenylene oxide, xanthone.

The compounds which can be prepared according to the invention must have at least two guanylhydrazone groups Contain, which also via aliphatic or alicyclic radicals with 1 to 10 carbon atoms on the Polycyclus can be bound. These guanylhydrazones act similarly to cardiac glycosides, i. i.e., they increase the force of contraction of the heart muscles. They are applicable as such or in the form of their salts with non-toxic organic 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 and hydrochloric acid. The products of the method according to the invention have a positive inotropic cardiac muscle effect, ίο which has been demonstrated in the following test arrangements could be:

1. Isolated spontaneously beating atrial preparation of the guinea pig. Method s.

P. H ο 11 ζ and E. Westermann, Naunyn-Schmiedebergs Arch. Exp. Path. and Pharmak., 225, p. 421 (1955), as well as G. Kroneberg and K. S tο e ρ e 1, Naunyn-Schmiedebergs Arch. Exp. Path. and Pharmak., 249, p. 394 (1964).

2. Measurement of the steepness of the intracardial pressure increase. Method see J. Ha macher, Naunyn-Schmiedebergs Arch. Exp. Path. and Pharmak., 244, p. 429 (1963).

3. Inhibition of the transport ATPase of the guinea pig heart (K. R e ρ ke and HJ P ο rtius, Experientia, 19, p. 452 [1963]).
Obtaining the transport ATPase according to T. Ko no and SP Collowick, Arch. Biochem. Biophys., 93, pp. 520-533 (1961).
Determination of the enzyme activity according to JV A udit ο re, Proc. Soc. exp. Biol. Med., 110, pp. 595-597 (1962).
35

Investigation results

Bisguanyl hydrazone dihydrochloride

of 1,8-diacetyl anthracene

Toxicity, mouse

6.3 to 8.0 mg / kg i.p. v.

Atrium, guinea pigs

Positive inotropic effect from concentrations of 3 · 10 ~ ⁸ g / ml. Cardiac muscle contracture and arrest at concentrations of 3 x 10 ~ ^s g / ml.

Intracardiac pressure rise steepness in the cat

Increase in the rate of pressure rise by 65 ° / _e after iv infusion of 2.8 mg / kg.

Transport ATPase, guinea pig

At concentrations of 10 ~ ^s molar = 49% inhibition.

Bisguanylhydrazone dihydrobromide
of 3,6-diacetyl-diphenylene oxide

Toxicity, mouse

20 to 25 mg / kg i.p. v.

g atrium, guinea pigs

Positive inotropic effect from concentrations of 3 · 10 ~ ⁶ g / ml. Heart muscle contracture and arrest at concentrations of 10 ~ ⁵ g / ml.

5 6

Bisguanylhydrazone dihydrochloride is obtained analogously by reacting 1 - (/ S-di-

des!, S-diacetyl ^ o-dihydroxynaphthalene (ethylammoethyl) -3-aminoguanidine or 1-nitro-

3-aminoguanidine with the diacetyl anthracene mixture

Toxicity, mouse the tetrahydrochloride of the bis-l- (ß-diethylamino-

8.0 to 90 mg / kg i ν ⁵ - 1% I) -guanylhydrazones or the bis- (l-nitroguanyl-

hydrazone) of the diacetylanthracenes, which melt ^{at 280 or atrium, guinea pigs 250} ° ^C.

Positive inotropic effect from concentrations
3 × 10 ^-5 g / ml. ₁₀ B eis ρ ie 1 2

Intracardial pressure increase gradient according to Hamacher 7.7 _{g of} 3,6-diacetyl-diphenylene oxide are in 250 ml

dissolved in hot absolute alcohol on the guinea pig and mixed with a

Solution of 9.5 g of aminoguanidine hydrobromide in

Increase in pressure rise by 105% ₁₅ 9 _m \ water and a few drops of hydrogen bromide after 0.05 mg / kg in acid. You narrow it in, suck it out

crystallizing precipitate and crystallized

". “,,.,, ,, ·. from methanol.

Bisguanylhydrazone Dihydrochlorid _Man ^ _{1 U1 Dihydrobromid des} 3,6-Diace-

des3,6-diacetyl-diphenylene _sulfide 2o tyldiphenylenoxyd-bisguanylhydrazone; Decomposition

Toxicity, mouse point 355 ° C.

12.5 to 16.0 mg / kg i.p. v. B e i s ρ i e 1 3

_rT , j - »,, ·, l> 2g aminoguanidine hydrogen carbonate are used in

Atrium, guinea pigs dissolved ₂₅ methanolic hydrochloric acid to pH = 2

Positive inotropic effect from concentrations and with a solution of 1 g of l, 5-diacetyl-2,6-di-

from 3 x 10 ~ ⁶ g / ml. Heart muscle contracture and hydroxynaphthalene added to ethanol. The mixture is left standstill at concentrations of 3 x 10 ^-5 g / ml. Stand under nitrogen at room temperature for 3 days,

stirs in ether, decants, dissolves the tough back

30 stood in ethanol and stirs again into ether.

Bisguanylhydrazone dihydrochloride The flakes that precipitate are suctioned off and several

of 1,5-diacetyl-naphthalene _rer e times boiled with acetone.

Toxicity, mouse 1.7 g of dihydrochloride of 1,5-diacetyl-

,. '. "" ". 2,6-dihydroxynaphthalene-bisguanylhydrazone. 280 ° C

8.0 to 9.0 mg / kg i.v. 35 (decomposition).

Atrium, guinea pig Example 4

Positive inotropic effects from concentrations of 2.68 g of 3,6-diacetyldiphenylene sulfide are found in the

of 3 x 10 ^ ⁷ g / ml. Heart muscle contracture from concentration dissolved in 30 ml of dimethylformamide and with a concentration of 3 · 10 " ⁶ g / ml. 40 solution of 2.2 g of aminoguanidine hydrochloride in

2.5 ml of water are added. Add 6 drops of concentrated

Intracardial pressure rise steepness according to Hamacher trated hydrochloric acid and heated for 1 hour on the on the guinea pig water bath. It is filtered, precipitated with ethyl acetate and

Increasing the pressure increase gradient to 60% ^Wä ^ ^ht, 5f ,, ^ ^Ster ° f * V ... -, _n .

after 0 05 mff / Icff im ⁴⁵ You get 3.7 g of dihydrochloride of 3,6-Diace-

nacn υ, υο mg / kg 1. m. tyldiphenylene sulfide bisguanylhydrazone. F 331 ° C (decomposition

setting).

All substances known up to the filing date with example 5
a cardiac glycoside-like effect are produced from plant

Extracts obtained are therefore natural substances. In contrast, 50 As in Example 3, 1,5-diacetyl-

it is the 2,6-dihydroxynaphthalene and 1,2-ethylene-3-amino-

new substances around the first synthetic substances guanidine hydrobromide the dihydrobromide of the 1,5-di-

with a cardiac glycoside-like effect. acetyl ^ ö-dihydroxynaphthalene-bis-il ^ -ethylene-guanyl-

The following examples illustrate the invention. hydrazone). M.p. 210 to 213 ° C (decomposition).

Example 1 . . ,

Example 6

2.6 g of a mixture of 1,5- and 1,8-diacetyl-

anthracene of melting point 185 ⁰ C in 70 ml analogously to Example 3, starting from

Dissolved chloroform, with a solution of 2.9 g of amino 60 l, 5-diacetyl-2,6-dihydroxynaphthalene and 1-ethyl

guanidine hydrogen carbonate in methanolic salt 3-aminoguanidine hydrochloride, the dihydrochloride

acid added (pH = 2) and 2 days at room temperature!, S-diacetyl ^ ö-dihydroxynaphthalene-bis-Cl-ethyl-

rature stirred. The precipitated lower guanylhydrazone is sucked. F. 180 ⁰ C (decomposition),
knock off and crystallize from ethanol with addition

of some water around. Yield 1.1g. 65.

The mixture obtained from the dihydrochlorides Example /

the bisguanylhydrazones of the diacetylanthracenes As in Example 3, 1,5-diacetyl-2,6-di-

melts at 335 to 337 ° C. hydroxynaphthalene and l-nitro-3-aminoguanidine das

10

Bis- (l-nitroguanylhydrazone) des 1,5-diacetyl-2,6-dihydroxynaphthalene. F. 160 ⁰ C (decomposition).

Example 8

Analogously to Example 1, the dihydrochloride of 1,5-diacetylnaphthalene-bisguanylhydrazone is obtained from 1,5-diacetylnaphthalene and ammoguanidine. F.> 300 ^a C.

Example 9

Analogously to Example 3, the dihydrochloride of 1,5-diformyl-2,6-dihydronaphthalene-bisguanylhydrazone is obtained from 1,5-diformyl-2,6-dihydroxynaphthalene and aminoguanidine hydrochloride. F. 295 ⁰ C (decomposition).

B e i s ρ i e 1 10

In a manner analogous to Example 3, 1,5-diacetyl-2,6-dihydroxynaphthalene is obtained and! '- (/ S-pyrrolidine-ethyl) -3-aminoguanidine-trihydrochloride the tetrahydrochloride of 1,5-diacetyl-2,6-dihydroxynaphthalene-bis- [l '- (j5-pyrrolidine-ethyl) -guanylhydrazone]. 192 ° C (decomposition).

Claims (1)

Claim: Process for the preparation of guanylhydrazones of aromatic polycyclic carbonyl compounds or their salts with non-toxic acids, characterized in that one polyeyelisehe aromatic compounds that have more than one keto or aldehyde carbonyl group included, either in a manner known per se a) with aminoguanidines of the general formula H ₂ NNC-NHB E NA
or converts their salts or 35 40 b) with thiosemicarbazides of the general formula H ₂ NNC-NH-B 45 50 condensed and the condensation products either directly or after their conversion in S-alkylisothiosemicarbazones with amines of the general formula c) with S-alkylisothiosemicarbazides of the general formula H ₂ NNC = H ₂ NA implements or 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 ₉ N - NH condensed and the hydrazones obtained with cyanamides of the general formula N ξ C - NH - B or S-alkylisothioureas in 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 Alicyclic or branched or unbranched or aliphatic substituted hydroxyl groups Radical with 1 to 6 carbon atoms, this radical 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 ^ R 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 substituted by one or more OH groups, alicyclic or branched or unbranched aliphatic radicals, each with up to 6 carbon atoms, which, optionally also via a nitrogen, sulfur or oxygen atom, can be connected to one another. 709 577/361 4.67 ® Bundesdruckerei Berlin