DE1695339C3 - 4,5-diphenylimidazole compounds - Google Patents

Description

CH

CH ₅ -CN

in which R is a hydrogen atom
Means ethyl group

or it has surprisingly been found that such a modified 4,5-diphenylimidazole is opposite pure 4,5-diphenylimidazole increased solubility in the materials mentioned, without the excellent dermatological properties of the 4,5-diphenylimidazole would be affected. the 44-diphenylimidazole compounds according to the invention show a strong antihistamine effect and have an expanding effect on the capillaries. While

However, the water solubility and also the solubility in glycerine, liquid paraffin and petrolatum of 4,5-diphenylimidazole both at 20 "C and at 70" C is very low, the solubility in the substances mentioned is both at 20 ⁰ C and greatly increased at 70 ⁰ C (with the exception of Petrolaum, which is solid at 20 ⁰ C), see Table 1 below.

Table 1

- ° Solvents

The invention relates to 4,5-Diphenyiimidazoi connections.

4,5-Diphenylir.iidazol is, for example, from DT-AS H 98 011 known. This 4,5-diphenylimidazole has a widening effect on capillaries. It's in water Petrolatum, paraffinum liquidum and glycerin are almost insoluble, so that it is difficult to make this connection to be incorporated directly into a medicinal product in which the aforementioned products are used as the basis will. This situation can be for example an ointment for dermatitis treatment, toothpaste, cosmetics such as cold bream, face milk, underlay lotion or lipstick mass, with the insolubility of 4,5-diphenylimidazole in said Materials has a detrimental effect as it is only dissolved in an organic solvent such as alcohol must be in order to be added to the base in this form.

The object of the invention was the 4,5-diphenylimidazole to change in such a way that its basic advantageous properties such as easy absorption, Capillary enlargement and increase of blood and lymph circulation without causing irritation sensitive skin can be maintained, on the other hand, the solubility in the mentioned Materials compared to that of pure 4,5-diphenylimidazole is increased at the same time should be ensured be that the improvement in the properties of 4,5-diphenylimidazole is not a disadvantage brings increased toxicity with it

This problem was solved by providing 4,5-diphenylimidazole compounds the general formula

H CH,
C-C-OH

/ I I

C ₆ H ₅ -CN HR

CH

CH ₅ -CN

in which R is a hydrogen atom or the ethyl group.

substance
Tue

! G)

DIPO
(ml / 1 g)

DIPE
(ml / 1 g

Distilled

water

2O ⁰ C

70 "C

Glycerin
2 (TC
70 ⁰ C

Liquid
paraffin

20 ⁰ C

70 ⁰ C

Petrolatum
20 ⁵ C
70 ⁰ C

300,000 ml
100,000 ml

6500 ml
4,500 ml

8 500 ml
5 500 ml

8 700 ml

9 760 ml
3 280 ml

150 ml
100 ml

1300 mi
500 ml

750 ml

10500 ml
4500 ml

300 ml
220 ml

1000 ml
430 ml

600 ml

In the table is 4,5-diphenylimidazole with Dl abbreviated while l- (4,5-diphenylimidazolyl) -2-propanol with DIPO and 1- {4,5-Diphenylimid-

• 45 azolyl) -2-ethyl-2-propanol was designated with DIPE.
Medicinal products to which compounds according to the invention are added, for example dermatitis ointments, effectively promote the peripheral blood circulation, strengthen the functions of the skin and increase the absorption of active components of the ointment in the same way as pure 4,5-dipfcr> nylimidazole, and likewise can A rash can also be cured with these compounds thanks to their anti-allergic and anti-inflammatory properties.

To determine the toxicity of the 4,5-diphenylimidazole compounds according to the invention, 4,5-diphenylimidazole and i- (4,5-diphenylimidazolyl) -2-propanol were used and 1- (4,5-diphenylimidazolyl) -2-ethyl-2-propanol dissolved or suspended in a suitable concentration in 1% aqueous gum arabic solution, and the test solution or suspensions obtained in this way were administered orally to mice with DD ancestry or injected subcutaneously. The solutions or suspensions were the mice in an amount of 0.1 ml to

hl 0.15 ml per day for five consecutive days entered. The results obtained in these investigations are shown in Table 2 below compiled:

Table 2 16 95 339 Total dose 4th Death rate 3 Imidazole compound (Deaths / (mg / kg) Total cases) treatment 1500 mg 0/10 4,5-diphenylimidazole 1500 mg 0/10 orally 1500 mg 0/10 I- (4,5-DiphenylimidazolyI) -2-propanol subcutaneous 1500 mg 0/10 injection ο ml 1500 mg 0/10 l- (4,5-DiphenyIimidazolyl) -2-ethyl- subcutaneous 1500 mg 0/10 2-propanoI injection orally subcutaneous

injection

example 1

75 g of propylene oxide and 5 ml of pyridine or triethylamine are added to 580 ml of 94% ethyl alcohol and mixed with 220 g of 4,5-diphenylimidazole. The whole is heated to a gentle boil in a water bath. The mixture is refluxed for 1.5 hours. The 4,5-diphenylimidazole dissolves completely. After cooling, the reaction mixture is kept at room temperature (20 ° C.) for 10 hours. During this process 1- (4,5-diphenylimidazoly) -2-propanol crystallizes out in the form of colorless platelets. The crystals are filtered off with suction, washed with cold 40% alcohol and then dried at low temperature. 223 g of crystals (A) are obtained. They have a melting point of 165-166 ° C. 100 ml of water are added to 500 ml of the filtrate obtained on suction. The mixture is kept at room temperature for 10 hours. 15 g of crystals (B) are obtained . The melting point of these crystals is lower than that of the crystals (A). 10 g of the crystals (A) are mixed with 200 ml of distilled water and dissolved by adding 10 ml of 10% hydrochloric acid filtered after thorough shaking. The clear solution obtained in this way is made alkaline by adding 28% strength aqueous ammonia solution. The precipitate is separated off in a vacuum filter and then dried at room temperature. The dried material is recrystallized from 80% ethanol. 8 g of purified crystals are obtained. These have a melting point of 167-168 ° C. The elemental analysis of the product showed:

dissolves completely. The reaction solution is then kept at room temperature (20 ° C.) for 10 hours. During this, 1- (4,5-DiphenylimidazoIyi) -2-ethyl-2-propanol crystallizes out in the form of colorless crystals. After filtering off, the crystals obtained are treated with cold 40% ethanol and then dried at room temperature. The yield is 200 g of crystals (A). These have a melting point of 146 ° C. 100 ml of water are added to 500 ml of the filtrate. The mixture is kept at room temperature for 10 hours, with 20 g of crystals ( B) apply. the melting point of these crystals (B) is lower than that of the crystals (a) For the crystals obtained, the pure product crystallized having a melting point of 148 -149 ° C according to the process described in example 1 purification processes.

Calculated

Found

C,% 77.67 77.54 H, % 6.52 6.41 N,% 10.06 9.82

Example 2

100g U-epoxy-2-methylbutane and 5ml N-methylpiperidine or triethylamine are added to 580 ml of 94% ethyl alcohol. After adding 220 g 4,5-Diphenylimidazole, the mixture is heated to a gentle boil in a water bath. One heats up 1.5 hours under reflux. The 4,5-diphenylimidazole

Calculated

Found

78.40
7.24
9.14

Example 3

78.21
7.40
9.40

In one with reflux condenser and drip collector two-necked flask provided 200 ml of ethanol, 70 g of 4,5-diphenylimidazole and 50 l-bromopropanol (2)

so introduced. Then a solution of 20.9 g Caustic soda dripped into 80 ml of distilled water over the course of about 1 hour through the dripping machine, the contents of the flask being kept at a low boil in a water bath. The reaction solution was nitrated while hot, and the filtrate was kept at room temperature (20 ° C) for 10 hours, whereby the product crystallized out. The crystals were suctioned off and treated with 40% ethanol and then washed with water. The total yield was 59 g of crystals having a melting point from 152-160 ° C. To 140 ml of the filtrate from which the ICrisialle had been separated, 50 ml Water added. The whole was kept at room temperature for 10 hours, with an additional 5 g of crystals incurred. The pure 1- (4,5-diphenylimidazolyl) -2-propanol with a melting point of 167-168 ° C was obtained by working up these crystals according to the in Example 1 described cleaning method obtained.

Example 4

Example 3 was repeated, except that 46 g of i-chloro-2-methyl-butanol (2) were used instead of 1-bromo-propanol (2), 55 g of crystals of 1- (4,5-diphenylimidazolyl) -2 -ethyl-2-propanol were obtained. The crystals have a lower melting point than the crystals (A) in Example 2 and almost the same as the crystals (B). By treating the filtrate from which the crystals were separated in the same manner as in Example 3, another 5 g amount of crystals was obtained. The pure product with a melting point of 148-149 ° C was obtained by treating the crystals according to the purification procedure described in Example 1.

Claims (1)

Claim: 4,5-DiphenylimidazoI compounds of the general formula H CHj CH ₅ - C- C-C-OH / I i -N H