DE1793272B2 - 2- (4'-CHLOROBENZYL) -PHENOLS, THE MANUFACTURING THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

20th

and Y = H or Cl or R = -C (CHj) ₃ and Y = Cl.

2. 2- (4'-3'-dichlorobenzyl) -6-nitro-4-tert-butylphenol.

3. 2- (4'-2'-dichlorobenzyl) -6-nitro-4-tert-butylphenol.

4. Process for the preparation of the 2- (4'-chlorobenzyl) phenols according to claim 1, characterized in that a phenol of the general formula is used in a manner known per se

OH

wherein R and R _{1 have} the meaning given in claim 1, with a benzyl chloride of the general formula

Cl-CH ₂

wherein Y has the meaning given in claim 1, reacts in the presence of zinc chloride and optionally nitrated the product obtained with nitric acid in glacial acetic acid.

5. Bacteriostatic agent containing a compound according to claims 1 to 3 as Active ingredient.

The invention relates to new bacteriostatically active 2- (4'-chlorobenzyl) phenols of the general type formula

OH

_{wherein R 1} = H, Cl or NO 2 and either R = —CH (CH ₃ ) ₂ or

CH ₃

C03

and Y = H or Cl or R = - C (CH ₃ ) ₃ and Y = Cl.

Two particularly effective representatives of these compounds are 2- (4'-3'-dichlorobenzyl) -6-nitro-4-tert-butylphenol and 2- (4'-2'-dichlorobenzyl) -6-nitro-4-tert-butylphenol.

The process according to the invention for the preparation of the compounds of the above general formula is characterized in that a phenol of the general formula is used in a manner known per se

OH

have, with a benzyl chloride of the general formula

35 ClCH,

wherein Y has the meaning given above, reacts in the presence of zinc chloride and optionally the compounds thus obtained are nitrated with nitric acid in glacial acetic acid. When condensation works advantageously in a solvent such as chloroform at reflux temperature.

The medicaments according to the invention can use one or more of the new compounds as an active ingredient contain. They can advantageously be administered orally in the treatment of infectious diseases will. The 6-nitro derivatives of the formula I, however, are particularly suitable for external use.

There are already 2- (4'-halobenzyl) phenols which are branched in the p-position to the hydroxyl group Alkyl groups are substituted and their bacterial

static effect known (cf. J. Org. Chem. 20, 1955, Pp. 1129 to 1134, and J. Med. Chem. 6, 1963, pp. 816 to 817). Comparative tests have shown, however, that the compounds according to the invention have a surprisingly greater bacteriostatic activity.

General production method

1 mol of phenol and 0.75 mol of mono- or diha'o-65 generated benzyl chloride or corresponding amounts are dissolved in 750 cm ³ 'of anhydrous chloroform. There are then 0.06 mol of comminuted zinc chloride, in which R and R, the meaning given above, are added, and it is

worked under gradual reflux for a period of 15 to 24 hours. After cooling 750 ml of water is added to the reaction mixture with stirring, it is decanted and the organic phase with water up to a pH value of 7 and then dried over sodium sulfate, The solvent is evaporated and the residue is subjected to distillation under reduced pressure. In accordance with this general procedure, the following compounds are made

example 1
2- (4'-chlorobenzyl) -4-isopropylphenol

As a respondent to the aforementioned Working methods are used:

40 g p-chloro-benzyl chloride,

41 g of 4-isopropylphenol,

18 g of molten zinc chloride,
200 ml of anhydrous chloroform.

The reaction mixture is refluxed for 21 hours (in two periods). The release of HCl stops after about 19 hours. 200 ml of cold, distilled water are added. After stirring and decanting, the organic phase is drawn off. The aqueous phase is extracted twice with 20 ml of chloroform. The combined chloroform extracts are washed four times with 25 ml of distilled water. The chloroform solution is dried over 75 g of anhydrous sodium sulfate. The solution obtained after filtration is clear. The solvent is removed first under normal pressure and then under reduced pressure (V ₂ millimeters of mercury).

A first fraction at 85 to 115 ° C consists of the unreacted raw materials. A second fraction at 160 "to 178 ° C consists of the almost pure desired product This fraction is recrystallized by redissolving in 60 mL of boiling petroleum ether, then -. Cooled to -10 ⁰ C. The product of the empirical formula C obtained ₁₆ H _n ClO (. Molecular weight = 260.5) melts at 57 ° C (measured on the Maquenne block).

In the same way, the following connections are made:

Example 2

2- (2 \ 4'-dichlorobenzyl) -4-tert-butylphenol
Mp. = 56 ° C.

Example 3

2- (2 ', 4'-dichlorobenzyl) -4-sec-butylphenol
C ₁₇ H ₁₈ Cl ₂ O; MG = 309.

= 170 ° C.
η * = 1.5796.

Example 4

2- (3 ', 4'-dichlorobenzyl) -4-sec-butylphenol
C ₁₇ H ₁₈ Cl ₂ O; MG = 309.
Bp _O2 = 160 to 162 ° C.
π ^{2ί 5} = 1.5779.

Example 5
2- (2 ', 4'-dichlorobenzyl) -6-chloro-4-tert-butylphenol

C ₁₇ H ₁₇ Cl ₃ O; MW = 343.5.
Kp.o ₂ = 153 to 156 ° C.
n ^2f * ⁵ = 1.5823.

55

60 Example 6
2- (2 ', 4'-dichlorobenzyl} -4-isopropylphenol

C ₁₆ H ₁₆ Cl ₂ O; MG = 295.
-O ₄ = 180 to 185 ° C.
= 1.5840.

The nitrated compounds according to the invention are made in the following ways:

^{150 cm 3 of} glacial acetic acid and 8 g of nitric acid d = 1.49 are introduced into a 500 cm ^{3 three-} necked flask, which is cooled on the outside by a bath with cold water and is equipped with a reflux condenser, dropping funnel, immersion thermometer and internal magnetic stirrer .

A solution of 17 g of the compounds of Example 2 in 50 cm ^{3 of} glacial acetic acid is added through the dropping funnel over a period of 20 minutes. The temperature of the water bath is then slowly increased for approx. 30 minutes until the internal temperature is 70 ° C., at which value it is maintained for 15 minutes. After cooling, the reaction mixture ^{is poured into 1000 cm 3 of} water, stirred vigorously and the crystallization of the oil is triggered by scratching or, if possible, by inoculating. The crystals obtained are centrifuged off, washed copiously with water and recrystallized from ethanol.

The yield of crystallized product is 60%.

Following this procedure, the following connections are made:

Example 7
2- (3 ', 4'-dichlorobenzyl) -6-nnro-4-tert-butylphenol

(produced by nitration of 2- (3'.4'-dichlorobenzylH-tert .-butylphenol)

C ₁₇ H ₁₇ Cl ₂ NO ₃ ; MG = 354.

Mp. = 106 ⁰ C.

Example 8

2- (2 ', 4'-dichlorobenzyl) -6-nitro-4-tert-butylphenol

(produced by nitration of the compound of Example 2)

C ₁₇ H ₁₇ Cl ₂ NO ₃ ; MG = 354.

Mp = 118 ° C.

The compounds according to the invention were examined toxicologically and pharmacologically as follows:

The acute toxicity per os was determined in mice according to the following test protocol.

Two sets of male and female mice weighing 18 to 22 g were examined 1 η of each group were 10 animals. The ones to be examined water-insoluble compounds were suspended in 10% gum arabic, and it became 0.4 ml administered by gavage per 20 g mouse.

The mice had fasted for two hours before the start of the experiment. The temperature and the behavior of the animals were / observed before your trial and then l _'2 hours and 3 hours after the typing. After this time, the animals were returned to their cage and observed for a few more days.

The number of dead animals was recorded daily. From this the lethal dose 50 (DL ₅₀ ) and the maximum tolerated dose (DMT) were determined.

The results are shown in the following table:

Table I.

link Used Compatible DL ₅ of the example solvent Maximum dose No ingAg 1 olive oil 0.5 1.7 2 olive oil 0.5 1.7 4th olive oil 1.0 2.4 5 olive oil 0.5 1.5

The results in Table I show that the toxicity of the compounds according to the invention always is equal to and often greater than 1.5 g / kg.

The bacteriostatic activity in vitro of the compounds according to the invention were compared with those of of known compounds compared.

The effectiveness was tested against the gram-positive Staphylococcus strain London.

The experiment is carried out in a nutrient medium with the following composition:

Indole-free bacteriological peptone 40% by weight

Sodium chloride 5% by weight

Glucose 2% by weight

pH value 7 to 7.2

Dilution series are made with the tested compounds. The dilutions go

ίο from 1 thousandth to 1 thousandth between the concentrations 1 thousandth and Vw thousandth. Of 10 thousandths to 10 thousandths Door thousandth the concentration is between Vio and _'100 thousandths of 100 thousandth to 100 thousandths for concentrations of ^l / ioo thousandth to a millionth. If the product was effective at a millionth dilution, a new millionth to millionth scale was set up beyond a millionth.

Two dilution series were made independently of one another. The results of both series must be identical. The tests were carried out after 24 hours. The results obtained are summarized in Table II below:

example R, R. Y m.i.c. ! -Χ ■ 10 ' 1 H CH (CH ₁ I ₂ H 800 2 H C (CHj) ₃ 2'-Cl 800 3 H CH (CH ₃ ) CH ₂ CH ₃ 2'-Cl 800 4th H CH (CH ₃ ) CH ₁ CH ₃ 3'-Cl 1000 5 Cl C (CHj) ₃ 2'-Cl 1000 6th H CH (CHj) ₂ 2'-Cl 1000 7th NO ₂ C (CHj) ₃ 3'-Cl 3000 8th NO ₂ QCHj) ₃ 2'-Cl 2000 Comparison connection a) H QCHj) ₃ H 600 b) H CH ₃ 3'-Cl 200 c) H "-C ₆ H ₁₃ 3'-Cl 10

m.i.c. ρ minimum inhibitory concentration.

Comparison compound a) is from J. Org. Chem. 20, 1955, page 1130, Table I, fourth compound from above, known; Comparative compounds b) and c) rind in I Med. Chem. 6, 1963, page 816, Table I and II under the Designation IV and VIII described. As Table II of the last-mentioned Liiuaturstelle shows, it bandelt in the case of comparison compound b) by one of the most effective compounds of the prior art

Claims (1)

Patent claims: 1. 2- (4'-chlorobenzyl) -j, henols of the general types formula OH -CH-CH ₂ -CH ₃ -CH ₃ wherein R ₁ = H, Cl or NO ₂ and ent- ι; neither R = —CH (CH ₃ ) ₂ or