DE1966002B - alpha-ketoaldehydes. Eliminated from: 1935380 - Google Patents

Description

where R stands for a nitro group.

The invention relates to α-ketoaldehydes of the general formula

Cl OH

R O

where R stands for a nitro group.

The α-ketoaldehydes of the above formula have therapeutic activity. They are especially known as O
-C-Cl

H, C

OHN

-c-c

HJ

O
-C-CH,

where Ar here and below for one of the substituents Cl and R containing phenyl radical. A benzoyl chloride is assumed, which is reacted with diazomethane, and that as an intermediate

p g

Effective against viruses or as a viricide. Experiments 30 resulting diazoketone is by means of

with cultures of flu and pox and pox viruses in eggs containing embryos showed the Effectiveness of these compounds against these infectious agents.

Hydroiodic acid reduced.

The same acetophenones can also be produced by the reactions shown schematically below will:

Il

Ar-C-Cl

H ₃ CCCC-OC ₂ H ₅
H ₂

Ar - C - C - H

C-OC ₂ H ₄

H ₂ SO ₄ , H ₂ O

Ar

C-CH,
O

Il

C - CH ₃

(a)

So it becomes a benzoyl chloride of the formula

O
Ar-C-Cl

condensed with acetoacetic ester in the form of the sodium derivative, whereupon that formed as an intermediate a-Benzoylacetoacetic ester (a) is hydrolyzed.

formula

Ar — C — C — C — OC ₂ H ₅
H ₂

as an intermediate by-product.

Another method for preparing the α-ketoaldehydes of the formula is by the following

An ethyl benzoyl acetate of the 55 scheme is also illustrated:

OHN OH O

HN

I I /

Ar-C-C

ENT ₂

Il I

- + Ar - C - C = O

N (b)

As mentioned above, by reacting diazomethane with a benzoyl chloride of the formula

Ar-C-Cl

The diazoketone obtained is thus condensed with triphenylphosphine, and the intermediate product

The triphenylphosphazine (b) formed is decomposed using nitrous acid. To isolate the a-ketoaldehyde from the reaction mixture, it is advantageous to convert it temporarily into the corresponding 1,3-diphenyl- 2- benzoyltetrahydroimidazole (c) by condensation with N.N'-dianilinoethane:

C ₆ H ₅
OH HN-CH ₂

Il I

Ar-C-C = O +

HN-CH ₂
C ₆ H ₅

IO

(C)

Essence of the starting material in the obtained mixture was determined by thin layer chromatography the metallic selenium separated by filtration, the solvent of the filtrate was removed under vacuum and evaporated in the heat and the residue was distilled using the temperature at 134 ° C / 0.6mm Hg boiling fraction was collected. So were 13 g (60% of theory) of a sparingly soluble in water and yellow oil which is soluble in the usual organic solvents is obtained.

Analysis for C ₈ H ₄ CINO ₄ (213,577):

Calculated ... C 44.99, H 1.89, N 6.56, Cl 16.60%; found .... C 44.30, H 2.21, N 6.20, Cl 16.28%.

Table 1 below shows the boiling points of some of the α-ketoaldehydes according to the invention of the formula I put together.

Table I.

O H

Il I,

Ar-C-C

QH ₅
N-CH ₂

N-CH ₂
C ₆ H ₅

The α-ketoaldehyde is produced by hydrolysis of the 1,3-diphenyl - 2 - benzoyltetrahydroimidazoles (c) recovered.

The a-ketoaldehydes of the formula I can be converted into their hydrate form (R ₁ = H) or a half acetal of the formula by treatment with water or the corresponding alcohol

II

be transferred.

The a-ketoaldehydes of the formula I and their hydrates and hemiacetals of the formula II can be in the form their derivatives of the formula

35

OHH
C-C-N
OR ₁

c — oh

111

obtained by condensation with p-aminobenzoic acid, are purified. The connections the latter formula are new.

The invention is explained in more detail using the following example.

example

m-nitro-p-chlorophenylglyoxal
(Formula I, Cl = p-Cl, R = m-N0 ₂ )

A mixture of 19.95 g (0.1 mol) of m-nitro-p-chloroacetophenone, 16.6 g (0.15 mol) of selenium dioxide, 50 cm ^{3 of} acetic acid and 10 cm ^{3 of} water was refluxed for 1 hour . After determining the

connection Cl p Boiling point in No. ¹⁵ OmIn ed 1 2-Cl 4-NO ₂ 118 / 0.5 2 2-CI 5-NO ₂ 137 / 0.8 3 4-Cl 3-NO ₂ 134 / 0.6 4th 4-Cl 2-NO ₂ 118 / 0.4 5 5-Cl 2-NO ₂ 128 / 0.6 6th 6-Cl 2-NO ₂ 110 / 0.3

The viricidal effectiveness of some of the invention Connections were determined by the following experiments.

Experiments with eggs containing embryos

Maximum tolerated dose (MTD) in embryos
containing eggs

The compounds were dissolved in saline solution, buffered to pH 7.2, containing 500 international units (IU) penicillin G and 0.5 mg streptomycin / cm ³ . There were decreasing doses of each compound dissolved ^{in 0.1 cm 3}

inoculated into the allantois or the urinary sac. Each dose was 9 days old in 3 embryos containing Injected eggs. The highest dose within 3 days did not cause mortality was established as the maximum tolerated dose (MTD).

Method for determining the effect against viruses

Leghorn hen eggs containing 9-day-old embryos and influenza virus A (allantoic fluid with a content of 10 ⁸ to 10 ⁹ EIT ₅₀

[EFD ₅₀ = mean egg infection dose] PR-8 strain adapted to eggs) was used. In addition, mouse pox virus ([ATCC] CAM [chorionallantoic membrane], which acts on the nerves) was homogenized and purified by centrifugation

with a content of 10 ⁶ to 10 ⁷ ELD ₅₀ [ELD = lethal dose for eggs] eggs adapted WR strain) was used.

Attempts at virus kill

For each dose, half of the maximum tolerated dose (0.5 MTD) dissolved in 10 cm ^{3 of} buffered saline was added to 10 ² EID ₉₅ , 10 ³ EID _95, and 10 * EID ₉₅ , respectively, and the 3 solutions were added for 1 hour

held at 37 ^° C. in water baths. Then the allantois of 5 eggs (for each dose) were ^{inoculated with 0.1 cm 3} each of one of the incubated solutions.

Determination of effectiveness

When influenza virus, the eggs were finally tested for 48 hours at 35 ° C and then stored for 12 hours at 4 ⁰ C and the presence of Hämoagglutinin or Blutagglutinin. For smallpox virus, eggs were kept at 37 ° C for 7 days and chick embryo mortality was determined.

The results of these tests are summarized in Table A below.

Table A.

MTD ") mg Eggs smallpox connection
No. μΜθ1 0.28 APR ₈ - virus*) 1.25 0.58 Virus*) 0 1 2.5 1.15 > 3 0 2 5 3.7 3 0 3 10 > 3 0 N- (a-ethoxy- 2 p-phenylphen- acyl) -p-amino- benzoic acid

") Maximum Tolerated Dose (MTD).

^b ) The numbers represent the difference between log EID _{95 of} the blind

try and log EID ,, of the treated eggs, where

EID = egg infection dose.

Table A shows the strong superiority of the compounds according to the invention the [N - (α - ethoxy - ρ - phenylphenacyl) -p-aminobenzoic acid], (= commercial product), especially in with regard to the APRg virus. The values given represent the virus infection concentration, which are rendered ineffective by half the toxic dose (0.5 MTD) of the substance in question is, logarithmically. Since toxicity is also taken into account in these values, they are a Measure of the therapeutic indi2es. Because of the logarithmic terminology, afterwards one means around one Unit greater than 10 times the therapeutic index.

Therefore, with respect to the APR _? -Virus 10- resp.

therapeutic indices more than 10 times as large as the commercial product.

Claims (1)

Claim:
α-Ketoaldehydes of the general formula Cl O
CC Therefore, the α-ketoaldehydes of the invention are Can be used as a medicine and disinfectant. The n-ketoaldehydes according to the invention can in a manner known per se, in particular by means of oxidizing the corresponding acetophenones Selenium dioxide. The acetophenones used to prepare the α-ketoaldehydes can be shown schematically by the following reactions shown are obtained: