DE1958238A1 - Halogen-substituted 1-oxy-3,3-dibromothiochromanones and processes for their preparation - Google Patents

Description

Seika Kaisha, Ltd.
No. 8, 2-chome, Kyobashi, Chuo-ku
Tokyo .

Halogen-substituted 1-0xy-3,3-dibromo-thiochromanones and methods of making them

The priority from Japanese patent application 85 193/68 filed on November 22, 1968 is claimed.

The invention "relates to 1-oxy-3,3-dibromo-6-halogenthiochromanones," which are new compounds which have valuable pharmacological properties. The subject of the invention also includes a process for the preparation of these new substituted thiochromanones _o

The new 1-Gxy-3,3-dibromo-6-halogen-thiochromanones according to the invention corresponded to the formula:

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in which X is a chlorine or bromine atom ". By experiment it was found that this new 1-oxy-3 »3-dibromo-6-halogen-thiochromanone anti-tumor agents and antivirals are.

Examples of the new compounds according to the invention are 1-oxy-3,3-dibromo-6-chloro-thiochromacDn and 1-oxy-3,3-dibromo-6-bromo-thioehromanone.

The inventive method for the preparation of the new 1-oxy-3,3-dibromo-6-halogen-thiochromanones, which of the formula I correspond, is carried out in such a way that a 3> 3-dibromo-6-hplogen-thioehromanone the formula:

in which X has the meaning already given, with a suitable inorganic oxidizing agents such as hydrogen peroxide, concentrated nitric acid, ohromic acid, or alkali permanganates or organic peracids such as perbenzoic acid, perphthalic acid or per-m-chlorobenzoic acid.

The 3j3-dibromo-6-halo-thiochromanones which are to be used as starting materials for the process according to the invention can easily be prepared by dehydration and cyclization of a p-halo-phenylmercaptopropionic acid of the formula: _χ CH ₂ COOH

J,

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_ 3 -

in which X represents a chlorine or bromine atom, by treatment made with concentrated sulfuric acid or polyphosphoric acid or similar will; this reaction gives a 6-halo-thiochromanone of the formula

0
X

in which X has the meaning already given. The latter Compound is then treated with 2 moles of elemental bromine in solution in a suitable solvent such as acetic acid. .

The method according to the invention can preferably be carried out in this way be that one is an oxidizing agent with a suspension or Solution of the 3,3-dibromo-6-halogenthiochromanone used as starting material in a suitable solvent such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, acetone, benzene, Reacts methanol, ethanol with the application of heat. An excess of aqueous hydrogen peroxide is preferably used as the oxidizing agent. After the reaction has ended the reaction mixture is allowed to cool so that the desired Oxidation product, namely i-Oxy ^^ - dibrom-ö-halogen-thiochromanon, can fail. The crystalline precipitate is filtered off, washed with water and dried. For further cleaning can a recrystallization from a suitable solvent z. B. Benzene can be made.

Example 1:

6.4 g of 3,3-dibromo-e-chloro-thiochromanone were dissolved in 60 ml of acetic acid

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dissolved with the application of heat. The solution obtained in this way was mixed with 25 oil of 30% strength hydrogen peroxide while stirring. Some of the starting material settled out during the addition of aqueous hydrogen peroxide, so that the reaction mixture became cloudy. A clear solution could be obtained by further heating. The reaction mixture was then heated for 5 minutes on an oil bath to a temperature corresponding to the boiling point of acetic acid and then removed from the oil bath. The reactor mixture was then cooled externally and set aside. The desired 1-oxy-3 »3-dibromo-6-chloro-thiochromanone fell as a crystalline precipitate aup. To complete the precipitation, some water was added to the mixture with stirring. The crystals were then filtered off, carefully washed with water and dried in a desiccator; 4.2 g of the desired product were obtained in this way. Recrystallization of the product from benzene gave 2.8 g of a purer product in the form of colorless prisms which had a melting point of 182 ^° C. (with decomposition).

Elemental analysis: ^%

Calculated for C _g HO ₂ SClBr ₂ ; C, 29.8 # H, l, 34 # Found: C, 29.19 # H, l, 32 #

Infrafot absorption spectrum (in Nu ^ oil):

<) SO 1028 cm " ¹ , VC = O 1698 cm"" ¹ Nuclear magnetic resonance spectrum (in CDCL,):

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H _r

H,

H ₁ .

ax

X 1.70 (d)

Χ 2.07 (d)

r.2.15 (q)
t 5.20

τ-5.80

AB quartet

When examining the influence of the solvent on · the nuclear magnetic resonance of the axial and equatorial protons of the methylene group in the 2-position showed that the other Sulfur atom introduced oxygen atom showed an axial arrangement. The 1-oxy-3,3-dibromo-6-chloro-thiochromanone corresponds to hence the following configuration:

H _E

ax

Example 2: - "

4 g of 3 »3-dibromo-6-bromo-thiochromanone were in the heat in 50 ml Acetic acid dissolved. 20 ml of 30 # strength aqueous hydrogen peroxide were added to the solution obtained in this way, with stirring. The mixture was heated to the boiling point of acetic acid for 5 minutes

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and then cooled from the outside. The reaction mixture was then turned off so that 1-oxy-3 *, 3-dibromo-6-bromo-thiochromanone as crystalline precipitate settled. Some water was added to complete the precipitation. The crystals formed were filtered off, washed carefully with water and in egg Dried desiccator; in this way 3f4 g of the desired was obtained Product. Recrystallization from ethanol gave 2.6 g of the pure product, which was colorless Prisms were present and a melting point of 179 ° C (with decomposition) exhibited.

Elemental analysis:

Calculated for C ₉ H ₅ O ₂ SBr ₃ : C 25.9 ^, H 1.20 # Found: C 25.84 #, H 1.99 #

Infrared absorption spectrum (in Nujol):

n) SO 1034 cm " ¹ , VC = O 1696 cm" ¹

The examination of the nuclear magnetic resonance spectrum showed that the oxygen atom in the 1-oxy-3 »3-dibromo-6-bromo-thiochromanone was also arranged axially, corresponding to the oxygen atom in the 6-chloro product according to Example 1

Example 3: y

The purpose of this example is to show that the product of Example 1, namely 1-0xy-3,3-dibromo-6-chloro-thiochromanone has a therapeutic effect, namely inhibiting the Spread of tumor cells works.

3 groups of mice, each group of 5 mice with

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an average body weight of 20 g were used as test animals. All of the mice in the three groups were ^{vaccinated with 2,000,000 Ehrlich cells for 1} sec. Mouse ascites tumor. 24 hours after vaccination, the mice of the first group were treated for 6 days with the test compound, ie the product from Example 1, and the compound was injected intraperitoneally at a dose of 20 mg per kilogram of body weight per day. The mice of the second group I were treated in the same way as the mice of the first group, but the | Test compound was injected intraperitoneally at a dose of 40 mg per kilogram of body weight per day, the mice of the third group were regarded as control animals and remained without treatment.

The mice of the first and second groups were further fed for 1 month; all mice survived. The mice were then dissected. There were no major abnormalities in the abdominal cavity of the mice. “In contrast, all mice of the third group were dead after a tionat * During dissection it was found that the mice showed clear symptoms of Ehrlich SvAscites tumor. "■■■■■ .. - i

The same was used to determine the toxicity of the test compound administered intraperitoneally to another group of 5 mice, and. although at a dose of 220 mg per kilogram of body weight. None of the muses were killed.

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Claims (1)

Expectations i-Oxy ^^ - dibromo-ö-halogen-thiochromanone of the formula in which X is a chlorine or bromine atom. 2.) 1-Oxy-3, ^ - dibromo-6rehlor-thioehromanone 3-r ) 1-Oxy-3,3-dibromo-6-bromo-thiochromanone 4.) Process for the preparation of 1-oxy-3,3-dibromo-6-halogenthiochromanone of the formula I according to claim 1, characterized in that a 3,3-mbromo-6-halothiochromanone of the formula 009822/1946 in which X has the meaning already given »with a suitable Neten oxidizing agent oxidized. 5 ») Method according to claim 4 # characterized in that one aqueous hydrogen peroxide used as oxidizing agent « for the applicantί Meissner & Bölte Meiji ieika
, 8 | 2-chdme, the It * 11 Patent attorneys 0Ü9822 / 1 <U6