DE1695339A1 - Derivatives of 4,5-diphenylimidazole and processes for their preparation - Google Patents

Description

Dfpl-liig. Klaus Neubecker ι Μην 1967 Patent attorney Düsseldorf, the '' Düsseldorf-EHer 1 R Q R Q 1 Q 6744 A "Strauss" cross53; Tel.722iai I O 3 3 0 * '3

Iwao Kawakami
Suginami-ku
Tokyo, Japan

Derivatives of 4,5-diphenylimidazole and processes for their preparation

The invention relates to derivatives of 4,5-diphenylimidazole and processes for their preparation.

It is known that 4,5-diphenyimidazole only dilates capillaries and is hardly contractile. Furthermore, it is almost insoluble in petrolatum, paraffinum liquidum and glycerine, and it is therefore difficult to bring this compound directly into a medicine using the aforementioned substances as a base. This can be the case , for example, with an ointment for dermatitis treatment and a toothpaste, or with cosmetics such as cold cream, face milk, underlay lotion and lipstick mass, and then the insolubility of 4,5-diphenylimldazole3 in the substances mentioned can be disadvantageous because it must first be dissolved in an organic solvent such as alcohol so that it can be added to the base in this form.

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The invention solves the problem of remedying these disadvantages and 4 ^ 5-diphenyliniidazole derivatives to create that characterized by new medicinal properties and in their chemical and physical properties dem 4,5-diphenylimidazole are superior.

Surprisingly, it was found that certain _r 4.5-Diphenylimidäzol-Deriväte strength Äntihistamin efficacy show expand Kapiilärgefäße and act kontraktierend long time. The 4,5-diphenyliraidazole derivatives according to the invention are characterized by the general formula

R-.

^C 6 ^H 5 -

L ι j

- C-OH

R *

CH

C _C H _C -C- ^ N

wthird

H, CH ₃ or C ^ CHj or C ^ H ₅ CHg ^ C ₂ H ₅ or M ^ CH- or G ₂

the. The aforementioned therapeutic effects have the advantage that they dissolve easily in hot as well as in cold petrolatum, Paraffinura liquidum, glycerine and polyethylene glucol. Viegan this good solubility can

turn them into suitable medicinal products where the aforementioned Compounds used as a basis are effectively incorporated e.g. in ointments and liquid masses for dermatitis treatment and in cosmetics such as cold cream, Face milk, pad lotion and lipstick mass. They ■ also have a pronounced therapeutic effect Guinea pigs experimentally caused asthma by inhalation of a dilute histamine solution.

A medicine to which one or more of the new compounds added, for example a dermatitis ointment, Effectively promotes peripheral blood circulation, strengthens the functions of the skin and increases absorption more effectively Components from the ointment, and at the same time can thanks to the antiallergic and antiinflammatory effectiveness of the compound a rash can be cured quickly. the Administration of the material in a plaster or English plaster does not lead to side reactions even over a long period of time.

(athlete's foot) actions. A means suitable for fufifIec1iie / -treatment, which contains a compound according to the invention is also effective against water eczema. The connection only needs in To be added in an amount of 0.02-1.5% by weight.

Cosmetics containing any of the compounds of the invention contain, promote proper peripheral blood circulation and accordingly strengthen skin functions Youth and beauty and at the same time support the absorption of nourishing ingredients of cosmetics and

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increase skin-regulating functions due to their anti-inflammatory properties Effectiveness. You can prevent dermatites in this way, which would affect a beautiful skin, and prevent skin reactions from cosmetics, they show no side effects even with long-term use.

Preference is given to dl-1- (4 ', 5 -diphenylimidazolyl) propanol (2) and dl-1- (4 ', 5 * -diphenylimidazolyl) -2-ethyl-propanol (2).

The invention also has methods for the subject which are the aforementioned 4,5-diphenylimidazole derivatives can be produced in a simple manner in high yield.

According to the invention, one of these methods is implementation of 4,5-diphenylimidazole with propylene oxide or a easily water-soluble butylene oxide derivative in the presence of a tertiary amine. For reaction with 4,5-diphenylimidazole come compounds of the following general formula

P. ι ³ R, - c - G-R Δ \ / I. 0

into consideration, in which R ₁ , R 2, R ₃ and R- have the same meaning as above. 1,2-epoxy-2-methylbut | m, 1,2-epoxy-2-äthy1- butane, 1, 2-epoxy-3-methylbutane, 2,3-epoxy-3-methylbutane and 2,3-epoxy 2,3-dimethylbutane are typical representatives.

The tertiary amines are trimethylamine, triethylamine, 1098 15/2180 - 5 -

Tripropylamine, tributylamine, ethyldimethylamine, methyl diethylamine, Pyridine, N-methylpiperidine or N-ethylpiperidine used with advantage.

Another method for preparing the compounds of the invention is to react 4,5-diphenylimidazole with 1-bromo-propanol (2) or generally with a 1-iIalogen-2-hydroxy compound, the butylene oxide derivatives in the presence of an alkaline substance. Connections of the general come here as participants in the Realction formula

R, R ₃

Γ I

R ₀ -CC-OH

² II

XR ₄

are considered, in which R., R ₂ , R ₃ and R ₄ again have the meaning given above, and X is Br or Cl. Mentioned in particular are 1-chloro-2-methyl-2-butanol, 1-chloro-2,5-dimethyl-2-hexanol, butylene chlorohydrin, isobutylene chlorohydrin and pentylene chlorohydrin.

The methods according to the invention are carried out as follows:

I. Propylene oxide or easily water-soluble butylene oxide derivatives and a small amount of a tertiary amine is added to alcohol. This solution comes with 4,5-Diphenylimldazole was added and it was boiling gently heated. After complete dissolution of the 4,5-diphenyl

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imidazoles, the solution is cooled to room temperature, whereby the desired product crystallizes out. After, filtering off the crystals with dilute alcohol washed and then dried. Since the crystals are of high purity, purification is usually unnecessary. Water is added to the filtrate obtained. A small amount falls again when it is left to stand Crystals out. The total amount of crystals obtained is 80-85% of theory.

II. 4,5-Diphenylimidazole and 1-bromo-propanol (2) or a 1-halo-2-hydroxy compound, which corresponds to a butylene oxide derivative, are mixed with alcohol. The solution is slowly mixed with alkali solution in a slight excess over the halogen compound while boiling slowly. The solution is filtered hot and the filtrate is cooled to room temperature, the desired product crystallizing out. The crystals are filtered off, washed first with dilute alcohol and then with water and finally dried. The crystals have a lower melting point than those obtained by the first process. The filtrate from which the crystals have been separated is mixed with water and left to stand; a smaller amount of crystals is obtained. The total amount of the crystals thus obtained reaches theory to 65% Zn. The product is used after further purification.

The invention is in the following with reference to the Seichnrang for example explained.

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The drawing is a graph of the pharmacological Properties of the new compound according to the invention dl-1- (4 *, 5'-diphenylimidazolyl) propanol (2). the The curve was obtained as follows: in 200 ml of Tyrode's solution A small living piece of marmot intestine was suspended from 37-38 ° C. When adding 0.1 ml of a 0.01% Bradykinin solution caused a strong contraction (point A). After a while, the solution with the strongly contracted tissue became 4 mg of the aforementioned compound added (point B), whereby the intestinal sample soon attained the state before the contraction. The figure shows So that dl-l-g *, 5'-diphenylimidazolyl) propanol (2) not only an irritant effect on the mucous membrane, but also a strong antagonistic effect on bradykinin shows.

Bradykinin is a peptide developed in 1949 by Silva U. coworkers was discovered, among other things, in the human blood. It causes histamine-like physiological effects, i.e. causes single |. strong ^ and sustained ^ contraction of the marmot intestine. It is believed to play a role in "allergic reactions."

The following examples show suitable processes for the preparation of the compounds according to the invention:

example 1

75 g of propylene oxide and 5 ml of pyridine or triethylamine will be added to 580 ml of 94% ethyl alcohol and with 220 g

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4,5-diphenylimidazole mixed. The whole becomes in one Water bath heated to a low boil. You cook 5 levels under reflux. The 4,5-diphenylimidazole dissolves in the process completely up. After cooling, the reaction mixture is kept at room temperature (20 ° C.) for 10 hours. This crystallizes dl-l- (4 ', 5'-Diphenylimida2olyl) - - " propanol (2) in the form of colorless platelets. The crystals are suction filtered, washed with cold 40% alcohol and then dried at room 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 by suction filtration. The mixture will be IO hours kept at room temperature. 15 g of crystals (B) at. The melting point of these crystals is lower than that of the crystals (&). 10 g of the crystals (A) are with 200 ml of distilled water mixed and dissolved by adding 10 ml of 10% hydrochloric acid. The solution will be a little cloudy mixed with 5 g of decolorizing charcoal and filtered after shaking thoroughly. The clear solution thus obtained is made alkaline by adding 28% 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 elementary analysis of the Product resulted in:

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_ 9 - 195339 Calculated: Found: 77.67 77.54 6.52 6.41 10.06 9.82

The reaction proceeds according to the following scheme:

U ^ H ₁ - - C ^ CH + CH- CH-
I ³
- CH- H
I. CH-
I 3 H ^C 6 ^H 5 ^-C - / * C - OH I. "> tl C, H _K - CN
■ * Il ^{x <}

Example 2

100 g 1,2-epoxy-2-methylbutane and 5 ml N-methy! -Piperidine or Triäthylamiri become 580 ml 94% ethyl alcohol added «After adding 220 g of 4,5-diphenylimidazole the mixture is heated to a gentle boil in a water bath. The mixture is refluxed for 1.5 hours. The 4,5-diphenylimidazole dissolves completely. The reaction solution is then kept at room temperature (20 ° C.) for 10 hours . During this, dl-1- (4, 5 -diphenylimidazolyl) -2-ethyl-propanol (2) in the form of colorless crystals. The solution, which contains the crystals, is in a vacuum filter filtered, and the separated crystals are washed with cold 40% ethanol and then with Room temperature dried. The yield is 200 g Crystals (A). These have a melting point of 146 ° C.

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100 ral of water are added to 500 ml of the filtrate in the vacuum filter. The mixture is kept at room temperature for 10 hours, 20 g of crystals (B) being obtained. The melting point of these crystals (B) is lower than that of the crystals (A). For these crystals give the pure product crystallized having a melting point of 148 - "149 ⁰ C according to the process described in Example 1 purification process is followed by an elemental analysis of C ₂₂ H _2Q OüJ."

Calculated: Found C f 78.40 78.21 II% 7.24 7.40 N% 9.14 9.40

The reaction can be written as follows:

II CII ₃

³ J ¹ CC-OH

■ ^C 6 ^H 5 " ^C *" ¹ J f 3 C ₆ H ₅ - C - NHC ₃ H ₅ 1 \ fjx j- r> vr _ η i. I ^

- JZ

CH

- C -N 0. C ₃ H ₅ C ₆ H ₅ - C - N

Example 3

Put in a reflux condenser and a dropping funnel Two-necked flasks were 200 ml iifthanol, 70 g 4,5-diplienylimidazole and 50 g of 1-bromo-propanol (2) were introduced. Then became a solution of 20.9 g of caustic soda in 80 ml of distilled water over the course of about 1 hour through the dropping funnel added dropwise, the contents of the flask in a water bath

BATH ORIGINAL

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schv / aeheirt boiling was kept. The reaction solution became filtered while hot, and the filtrate was 10 hours kept at room temperature (20 ° C), the product crystallized. The crystals were filtered off with suction and washed with 40% ethanol and then with water. the The total yield was 59 g of crystals with a melting point of. 152-160 ° C. To 140 ml of the filtrate from which the crystals were separated, 50 ml of water was added. The whole was 10 hours at room temperature held, whereby a further 5 g of crystals were obtained. The pure crystallized product with a melting point of 167158 ° C was obtained by working up these crystals according to the purification method described in Example 1. The reaction proceeds according to the following scheme:

H II ³

f C-C-OH

^C 6 ^H 5 ""? ' ^N v'. -? ^H 3 C ^ H ₁ - - C - HHH

\ ij \ _- ri, - - v ^ - vi η. ^{1 6 5} Il \

.. CH + CH ₉ -CH- }. \ _

i | / J ² I ■■ - ^CH

C-N Br OH

Example 4 ...-. '

Example 3 was repeated, but instead of the l-bromo-propanol (2) 46 g l-chloro-2-methyl-butanol <2) used, 55 g crystals of dl-l- (4 ', 5'-diphenylimidazolyl) -2-ethyl-propanol (2 ) were obtained. The crystals have a lower melting point than the crystals (A) in Example 2 and almost the same as the crystals (B).

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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 process described in Example 1. The reaction proceeds as follows i

.- C

C ₆ H ₅ -C

-N

CH + CH ₂ Cl

CH.

C - C ₀ H ₁ -

! ^{2 5}

OH

6 5 μ

C - OH

^C 2 ^H 5

.-C-H

'CH

The following table shows the solubility of dl-l- (4 ' _r 5' Dipheny! ImidazoIyI) -propanol (2)

^ * ^^^^ substance
Temperature "* -" · - «^ white
Soft paraffin liquid
paraffin Glycerin 70 ° C - 100 ° C approx. 0.6% about 0.6% approx. 6.5% 40 ° C about 0.1% approx. 1.5%

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Claims (9)

Claims 1. 4,5-diphenylimidazole derivative, characterized by the following general formula 11 , 0. -C- OH - c - C - N CH wherein B ₁ - ^R 2 ⁼ R, = H, Ch ₃ or C ₃ H ₅ H, CH ₃ or C ₂ Ii ₅ H, - CH ₃ or C ₃ H ₅ or CH (CH ₃ ) H, CH- or C ₅ II ₁ . are. 2. 4,5-diphenylimidazole derivative according to claim 1, characterized by the general formula H CH- Sl I 1 3 - C - OH CAU -CM HH CH C ₆ H ₅ - C - 3. 4 8,5-diphenylimidazole derivative according to claim 1, characterized by the general formula H CII., r 1 ³ c -c- oh C ₆ E ₅ -C- C ₂ H ₅ C ₆ H ₅ -C S. 1098 15/2180 4. Process for the preparation of 4,5-diphenylimidazole derivatives according to Claim 1, 2 or 3, characterized in that that one 4,5-diphenylimidazole in the presence a tertiary amine with propylene oxide or a light converts soluble butylene oxide. 5. The method according to claim 4 _? characterized in that 1,2-epoxy-2-methy! butane, 1,2-epoxy-2-ethy! butane, 1,2-epoxy-3-methylbutane, 2,3-epoxy-3- or
methylbutane is used as 2,3-epoxy-2,3-dimethylbutane will. 6. The method according to claim 4 or 5, characterized in that the tertiary amine is trimethylamine, triethylamine, Trip ^ pylamine, tributylamine, Ethy! Dimethylamine, methyl diethylamine, Pyridine, N-methylpiperidine or M-ethylpiperidine is used. 7. Process for the preparation of 4,5-diphenylimidazole derivatives according to one of claims 1-3, characterized in that 4,5-diphenylimidazole in the presence an alkaline substance with l-bromopropanol (2) or with a l-halo-2-hydroxy compound, which is a Butylene oxide DerJ / at corresponds, converts. 8. The method according to claim 7, characterized in that the 4,5-diphenylimdiazole with l-chloro-2-methyl-2-butanol, l-chloro-2,5-dimethyl-2-hexanol, butylene chlorohydrin, Isobutylene chlorohydrin or pentylene chlorohydrin is implemented. 10 9 8 15/2180 - 15 - 9. Use of 4,5-diphenylimidazole derivatives according to Claim 1, 2 or 3 for influencing the vessels, in particular as antihistainic and anti-inflammatory drugs. 109815/2180 Blank page