DE2023711C - - Google Patents

Description

The present invention relates to new N-acryloyl-5-chloro-2-aminobenzhydrols the general formula

N-CO-CH = CH ₂

(I)

30th

in which R denotes water or the methyl group. The N-acryloyl-5-chloro-2-aminobenzhydrols of the formula I are z. B. by splitting off hydrogen halide from suitable N-zf-halopropionylaminobenzhydrols the formula

(II)

35

N - CO - CH ₂ - CH ₂ - shark

To implement 40 benzhydrols and, without isolating these compounds, to convert them into the N-acryloylaminobenzhydrols according to the invention by adding alkali metal hydroxide.

Finally, also ^ -halopropionic acid esters react with aminobenzhydrols, optionally using a suitable solvent, such as. B dimethylformamide, and in the presence of basic compounds that eliminate hydrogen halide _; g promote, at higher temperatures with formation of ckr N-acryloyl-aminobenzhydrole.

The N-acryloyl-5-chloro-2-aminobenzhydrols of the formula are characterized by a surprising chemotherapeutic effect, as it has not yet been described in this class of compounds has been. They are in animal experiments after oral acceptance against fungi, for example Trichophyton mentagrophytes. effective, and better than griseofulvin.

The tests were carried out on guinea pigs that had been infected with Trichophyton mentagrophytes had been infected. Two series of tests were carried out:

a) Oral application

A group of infected test animals received N - acryloyl - 5 - chloro - 2 - aminoLenzhydrol orally in Gelatin capsules. The animals were administered 260 mg kg body weight daily. As a reference substance served griseofulvin in a daily dose of 250 mg / kg body weight.

The duration of treatment was 14 days.

b) Local application

A 0.5% solution (solvent 70% alcohol) was applied to the skin of the infected animals. of N-acryloyl-5-chloro-2-aminobenzhydrol applied. Nystatin was used as a comparison substance 6000 U / ml solution (70% alcohol) used.

Here, too, the duration of treatment was 14 days.

A group of untreated infected test animals was also observed as a control.

The treatment results are summarized in the table.

wherein Ha ^{1 is} a halogen atom, for example chlorine or bromine, and R dis has the above meaning, prepared in the presence of a suitable base. Suitable bases which split off hydrogen halide are the alkali metal and alkaline earth metal hydroxides or carbonates, such as. B. sodium hydroxide or carbonate.

The N- / i-halopropionylaminobenzhydrols of the formula (II) used as starting compounds are also new. They can be obtained by acylation of appropriately substituted or unsubstituted aminobenzhydrols with / i-halopropionyl halides. However, suitable aminobenzophenones can also be acylated with / f-halopropionyl halides and subsequently by reduction, e.g. B. with an alkali metal borohydride, are converted into the N - ji - halopropionyl - aminobenzhydrols.

But it is also possible to have substituted or unsubstituted ones Aminobenzhydrols with i-halopropionyl halides in the presence of an alkali metal carbonate to the corresponding N-Zi-halopropionyl-amino-

45 Preoarpt

control

N-acryloyl-5-chloro-2-aminobenzhydrol

a) orally

b) local

Oral griseofulvin

Nystatin locally

Number of animals

Treatment success positive I negative

10

The toxicity of the compounds according to the invention is extremely low. The LD ₅₀ of N-acryloyl-5-chloro-2-aminobenzhydrol in rats after oral administration is over 4000 mg / kg body weight.

In the following the invention is based on exemplary embodiments explained in more detail.

Example!

a) 2Γ g of 5-chloro-2-aminobcnzophenone are dissolved in 300 ml of acetone. To this end, 28 g of powdered crystal soda (Na ₂ CO., · 10H ₂ O) are suspended. Under

Stir 14 g, / - chloropropionyl chloride during Added dropwise for 15 minutes. Carbon dioxide develops vigorously and the temperature rises to 35 to 40'C.

Care is taken by cooling with water. that the temperature does not exceed 40 ⁰ C. When the addition of / i-chloropropionyl chloride is complete, the mixture is heated on the water bath for a further 15 to 20 minutes, then it is cooled and the reaction mixture is introduced into 1000 ml of dilute hydrochloric acid. An oil separates out. which soon solidifies in crystalline form.

M.p .: 58 to 6O ⁰ C Yield: 34g N - /) '- chloropropionyl-S-chloro-l-aminobenophenon.

By dissolving in methanol. Decolorization with activated charcoal and the addition of water turn colorless needles receive.

Fp .: 68 to 70 ^c C.

b) 30 g of N-f (-Ch! ^ rpropionyl-5-chloro-2-aminobenzophenone are dissolved in 150 ml of methanol. 10 ml of water were added and 2.8 g of sodium borohydride were added in portions admitted. After the addition of sodium borohydride has ended, the mixture is left for a few minutes put, diluted with water and acidified. A colorless oil separates out, which is then left in the refrigerator crystallized in a short time.

Mp .: 74 to 76 C: Yield: 28 g of Ν-, ί-chloropropionyl-5-chloro-2-aminobenzhydrol.

After recrystallization from aqueous methanol, the pure product melts at 84 to 86 C.

c) _{14 g of N-i} -chloropropyl-5-c ^L 'lor-2-aminobenzhvdrol are dissolved in 50 ml of methanol. The solution is added to sodium hydroxide solution (2 g of sodium hydroxide, dissolved in 6 ml of water) within 2 minutes while stirring. The temperature rises by 10 to 15 ^C C; at the same time table salt separates out. One stirs

Another 5 minutes, pour the reaction mixture into water and adjust to pH 3 by adding hydrochloric acid. The oil that separates out crystallizes after a short time. The crystals are suctioned off and with Water washed (crude melting point: 100 to

102 ⁰ C). The pure product is obtained in the form of colorless needles by dissolving in methanol, decolorizing with activated charcoal and carefully precipitating with water.

M.p .: 106-108 ° C; Yield: 10 g of N-acryloyl-5-chloro-2-aminobenzhydrol.

In the same way, N-acryloyl-N-methyl-5-chloro ~ -2-aminobenzhydrol (m.p .: 100 to 102 ⁰ C) of 5-chloro-N-methyl-2-aminobenzophenone obtained advertising

^the · example 2

15 g of 5-chloro-2-aminobenzhydrol are dissolved in 80 ml of acetone, 14 _{g of powdered Na 2} CO _{3 -IOH 2} O are added, and 7 g of ff-chloropropionic acid chloride are added with stirring. After the addition, stirring is continued for 10 minutes on the water bath and 30 ml of water and a solution of 0.5 g of sodium hydroxide in 5 ml of water are then added. It is stirred for another 10 minutes, then precipitated with water and adjusted to pH? With hydrochloric acid. set; the oil that separates out solidifies after a short time.

Yield: 13 g of N-acryloyl-S-chloro ^ -aminobenzhydrol.

Claims (1)

Claim:
N - acryloyl - 5 - chloro - 2 - aminobenzhydroles der general formula N - CO - CH = - CH ₂ CHOH in which R is hydrogen or the methyl group.