DE1518392B - - Google Patents

Description

. The invention relates to 3,5-diiodo-4- (3,5-dimethyl-4-hydroxy- or -methoxy-phenoxy) -phenethyl alcohol and derivatives of the general formula

CH

RO

CH

in which R and R 'each have a hydrogen atom, each an acetyl group or R a methyl group and R' a hydrogen atom mean, and a process for their preparation, which is characterized in that a compound of the general formula

RO

in which R is as defined above, is reduced in the presence of an inert solvent at a temperature between -20 and 50 ⁰ C with diborane and optionally the thus obtained phenoxy-phenethyl alcohol acetylated.

The compounds according to the invention have hypocholesteremic activity.

The preparation of representatives of this class of compounds is in Journal of Biological Chemistry, 235, 3292 (1960).

The preparation according to the invention can in an inert solvent such as tetrahydrofuran, ether, Diäthylenglykoldi'methyläther, dioxane, at temperatures between about -20 and 5O ⁰ C, between about 0 and 30 ⁰ C are preferably carried out.

The carboxylic acids which can be used for the preparation of the compounds according to the invention are

3,5-Diiodo-4- (3,5-dimethyl-4-methoxyphenoxy) -

phenylacetic acid;
3,5-Diiodo-4- (3,5-dimethyl-4-hydroxyphenoxy) -

phenylacetic acid.

These 4-phenoxy-3,5-diiodo-phenyl-acetic acids can be prepared by known processes (see e.g. M e 11 ζ e r and coworkers, The Journal of Organic Chemistry, 22, 1577 [1957]).

In the case of the one described by M e 11 ζ e r and co-workers In the process, the acetic acid derivatives are obtained by condensation of a 4-alkoxyphenol with an (4-mesyloxy-3,5-dinitro-phenyl) -acetic acid alkyl ester or a 4-tosyloxy-3,5-dinitro-phenyl) -acetic acid alkyl ester with formation of the [4- (4-alkoxyphenoxy) - 3,5 - dinitro - phenyl] - acetic acid alkyl ester, Reduction of the nitro groups to amino groups, replacement of the amino groups by iodine via the diazonium compound according to Sandmeyer and hydrolysis of the resulting [4- (4-alkoxyphenoxy) -3,5-diiodo-phenyl] -acetic acid alkyl ester with formation the corresponding [4- (4-alkoxyphenoxy) -3,5-diiodophenyl] acetic acid. The [4- (4-alkoxyphenoxy) -3,5-diiodo-phenyl] -acetic acid alkyl ester can also be dealkylated or saponified by heating with a mixture of acetic acid and hydriodic acid, the corresponding [4- (4-hydroxyphenoxy) -3,5-diiodo-phenyl] acetic acid is obtained.

Substituted 4-alkoxyphenols are obtained after the Elbs reaction [Journal of the Chemical Society (London) 1948, p. 2303]. For the above Process suitable 4-alkoxyphenols are, for. B. 4-methoxyphenol, 4-ethoxyphenol, 4-propoxyphenol, 4-butoxyphenol, 4-isobutoxyphenol, 3-methyl-4-methoxyphenol, 2-methyl-4-methoxyphenol, 3-methyl-4-propoxyphenol, 2,5-dimethyl-4-methoxyphenol, 2,3-dimethyl-4-methoxyphenol, 2-methyl-4-methoxyphenol, 2,3-dimethyl-4-butoxyphenol, 2 - isopropyl - 5 - methyl - 4 - methoxyphenol, 2,3,5-trimethyl-4-methoxyphenol, 2,3,5-trimethyl-4-propoxyphenol, 2,3,5,6-tetramethyl-4-methoxyphenol, 2,3,5,6 - tetramethyl - 4 - propoxy - phenol, 3,5 - dimethyl - 4 - methoxyphenol, 3,5 - diethyl-4-methoxyphenol, 3,5-dibromo-4-methoxyphenol, 3,5-dichloro-4-methoxyphenol.

Another method of making the acetic acid derivatives is in British Patent Specification 882,401 described, according to which a nitro-oxazolone derivative with a mixture of acetic acid and hydrohalic acid is reacted to form the corresponding pyruvic acid derivative, which then is reacted with hydrogen peroxide in alkaline solution to form the nitroacetic acid derivative, the nitro group of which is reduced to the amino group, which is then replaced by iodine according to Sandmeyer.

Another process for the preparation of the phenoxyphenylacetic acids is described by Z i e g 1 e r and coworkers in The Journal of Organic Chemistry, 27, 3335 and 3336 (1962).

The diacetates (formula I, R and R '= acetyl) can be prepared by reacting the not esterified (4-phenoxy-3,5-diiodophenyl) ethanol with an acetylating agent, e.g. B. acetyl chloride or Acetic anhydride.

example 1

a) 3,5-Diiodo-4- (3,5-dimethyl-4-hydroxyphenoxy) -phenethyl alcohol

A solution of 2.0 g of 3,5-diiodo-4- (3,5-dimethyl-4-hydroxyphenoxy) -phenylacetic acid in 20 ml of tetrahydrofuran was treated with a slow gas stream of diborane and nitrogen. A vigorous reaction occurred with evolution of hydrogen, and after a reaction time of about 5 minutes a white solid separated out. The supply of diborane was stopped, then 20 ml of tetrahydrofuran were added and the mixture was stirred at room temperature for 30 minutes. 20 ml of water were then added and the tetrahydrofuran was distilled off under reduced pressure; The solid white product was filtered, washed well with water and dried under reduced pressure at 6O ⁰ C. Recrystallization from benzene gives colorless prisms and further recrystallization from ethanol-water gives 3,5-diiodo-4 - (3,5 - dimethyl - 4 - hydroxyphenoxy) phenethyl alcohol with a melting point of 193 ° to 197 ° C. An analytically pure Sample with a melting point of 197 ° to 198.5 ° C. was obtained on recrystallization from ethanol.

Analysis for C ₁₆ H ₁₆ I ₂ O ₃ :

Calculated ... C 37.67, H 3.16, I 49.76;
Found ... C 38.03, H 2.88, I 49.34.

b) 3,5-Diiodo-4- (3,5-dimethyl-4-acetoxy-phenoxy) -phenethyl acetate

1.0 g of 3,5-diiodo-4- (3,5-dimethyl-4-hydroxyphenoxy) -phenethyl alcohol was treated with 1 ml of acetic anhydride in 10 ml of pyridine at 25 ° C. for 16 hours. The reaction mixture was poured into 100 ml of water; when left to stand, 1.1 g of amorphous solid were obtained which, recrystallized from a hexane mixture with a boiling point of 61 to 72 ° C., gave 0.93 g of crystalline white product. After repeated recrystallization from hexanes to afford 3,5 - diiodo - 4 - (3,5 - dimethyl - 4 - acetoxy - phenoxy) -phenäthyl-acetate melting at 139.5 to 140.5 ⁰ C.
Analysis for C ₂₀ H ₂₀ I ₂ O ₅ :.

Calculated ... C 40.52, H 3.40, I 42.82;

Found ... C 40.85, H 3.37, I 41.94.

Example 2

3,5-Diiodo-4- (3,5-dimethyl-4-methoxyphenoxy) -phenethyl alcohol

According to the method described in Example 1, 3,5-diiodo-4- (3,5-dimethyl-4-methoxyphenoxy) -phenethyl alcohol, starting from 3,5-diiodo-4- (3,5-dimethyl-4-methoxyphenoxy) phenylacetic acid. The product melted at 134.5-135.5 ° C.

Analysis for C ₁₇ H ₁₈ I ₂ O ₃ :

'Calculated .... C 38.95, H 3.46, I 48.42; found ... C 38.81, H 3.65, I 48.5.

Atherosclerosis is characterized by the deposition of degenerate fats on the arterial walls; the mechanism leading to this has not yet been clarified. However, it has been observed that in humans just as there is hypercholesteremia in animals with atherosclerosis. The hypercholesteremia goes essentially due to excess cholesterol in the blood serum. While the causes of hypercholesteremia and the role they play in atherosclerosis and related diseases plays, have not yet been completely clarified, one is already making an intensive effort to keep the cholesterol level in the Lower blood and tissue in the case of symptoms associated with high cholesterol are. It has long been known that certain substances such as sitosterol, corn oil and nicotinic acid, are able to lower the cholesterol levels in the blood and tissues somewhat, either by they intervene in the absorption of cholesterol brought in from outside with food or by doing facilitate the elimination of cholesterol. However, the main interest today is in substances that are able to intervene in the production of endogenous cholesterol in the liver and thereby allow more effective control of cholesterol levels.

It has been found that the compounds according to the invention are able to reduce the cholesterol content noticeably decrease in blood and tissue by increasing the breakdown and excretion of cholesterol out of the body.

The dosage of the active ingredients must be case-by-case depending on the age and weight of the patient (or of the animal to be treated), responsiveness to medication, severity of the case to be treated and form of administration can be determined. Single doses between about 0.5 and 500 mg of the active ingredient are possible, preferably about 2 to 50 mg are given 1 to 4 times per day. The administration to human patients should only be done as directed by a doctor. In veterinary medicine, a dosage can be worked according to weight.

The above-mentioned active ingredients can be mixed with supplementary substances by means of which advantageous combinations of properties tailored to the respective situation can be achieved. Such substances are z. B. other hypocholesteremic agents such as 22,25-diazo-cholestanol, the D-isomer of 3,5,3'-triiodo-hyronine, and thyroxine-like compounds such as sodium L-thyroxine and sodium D-thyroxine; Glucocorticoids such as hydrocortisone, prednisolone, 6a-fluorprednisolone and 6a-methylprednisolone; Anticoagulants such as heparin, 2-diphenylacetyl-1,3-indanedione, polyethylene sulfonate and dicumarin or its derivatives; Vitamins such as nicotinic acid, ascorbic acid, tocopherols, vitamin B ₁₂ and pyridoxine hydrochloride; Estrogens such as estradiol and ethinyl estradiol; Androgens such as testosterone, methyltestosterone, and fluoxymesterone; Mixtures of estrogens and androgens such as estradiol and testosterone; unsaturated fatty acids or esters thereof such as sunflower oil, lecithin, corn oil, linolenic acid or its esters, antibiotics such as neomycin; Ion exchange resins such as synthetic strongly basic anion exchange resins having quaternary ammonium functional groups bonded to a styrene-divinylbenzene copolymer; Analgesics such as acetylsalicylic acid; hyoglycemic agents such as tolbutamide; compounds related to the synthesis or metabolism of cholesterol, such as a-phenylbutyric acid, α - ρ - biphenylbutyric acid and α - (ρ - chloro - phenoxy) - isobutyric acid - ethyl ester; lipotropic agents such as choline and inositol; Amino acids such as dl-methionine, taurine and glycerine; Sterols such as sitosterol and other plant sterols; Diuretics such as ethoxazolamide, acetazolamide and hydrochlorothiazide; anorexigenic agents such as amphetamine; cardiovascular agents (including vasodulators and hypotensive agents) such as chloroisondamine chloride, hexamethonium chloride, and pentaerythritol tetranitrate. The amount of these additives in a dosage unit of the agents according to the invention should not exceed the normal single dose of these substances.

The active compounds according to the invention are expediently used for administration to mammals and birds in tablets, pills, capsules, powders, wafers, granules, sterile paranteral solutions or suspensions in aqueous or oily medium, oral aqueous or oily dispersions including syrups and elixirs or the like incorporated.

For the production of solid preparations, such as tablets, the active ingredient is mixed with a conventional carrier, such as corn starch, lactose, dicalcium phosphate, talc, stearic acid, calcium stearate, gum acid or functional similar materials. The tablets or pills can be constructed in the shape of a shaft, if one longer or delayed effects or a certain sequence of effects of different components is strived for. The tablets can e.g. B. contain a drug inside that of a second is wrapped. The two components can

be separated from each other by a layer which is only soluble in the intestine and which is not broken down in the stomach, so that the inner active component reaches the intestine undamaged. For the formation of these. Only soluble in the intestine Numerous substances, such as polymeric acids or mixtures of polymeric ones, are suitable for the layer Acids and shellac, shellac and cetyl alcohol, cellulose acetate phthalate (U.S. Patent 2 196 768). A particularly favorable coating that is only soluble in the intestine consists of a styrene-maleic acid copolymer in a mixture with other known substances that contribute to the property of the coating itself only to be released in the intestine.

Liquid forms of administration of the substances obtainable according to the invention are aqueous dispersions, aromatic syrups, emulsions or suspensions with edible oils such as corn oil, cottonseed oil, Sunflower oil, soybean oil, elixirs and like pharmaceutical carriers. Suitable dispersing or suspending agents for the production of aqueous suspensions are synthetic and natural gums, such as tragacanth, gum arabic, alginates, dextran, methyl cellulose, polyvinylpyrrolidone, gelatin.

When preparing injectable solutions or suspensions, it is expedient to use the usual Preservatives, buffers, isotonic agents and suspending agents. Suitable preservatives are z. B. chlorobutanol, myristyl-8-picolinium chloride, Benzyl alcohol, 4-hydroxybenzoic acid methyl and propyl ester and sodium ethyl mercuric thiosalicylate. Potassium chloride is a preferred isotonic agent. Suitable suspending agents are e.g. B. Polyethylene glycol 4000 and 6000, polyvinylpyrrolidone, dextran, methyl cellulose and surfactants Agents such as polyoxyethylene sorbitan monooleate.

Test report

To the superiority of the compounds according to the invention as a hypocholesterolemic agent against the 4-p-hydroxyphenoxy-3,5-diiodophenethyl alcohol, which is known for this effect (designated as V in the table below), the following comparative tests were carried out.

Hypercholesteremia was caused in male Sprague-Dawley rats fasting 220 g. By feeding them a high cholesterol diet containing 10% coconut oil as a fat source and 18% casein with 0.2% added methionine as a protein source. The test compounds, which were suspended in 0.25% strength methyl cellulose in concentrations such that 1 cm ^{3 of} the vehicle per 100 g of body weight were required, were administered orally to groups of 10 rats each. Control groups received the vehicle only. The rats, weighed three times per week, were fed ad libitum until 17 hours before the end of the experiment (14 days). After treatment with sodium cyclopentyl allyl barbiturate at a concentration of about 80 mg / kg, blood was withdrawn from the aorta. At the end of each experiment, feed consumption and weights were recorded.

The total amount of sterol was determined by the method of Z a k, et al., Analytical Chemistry 26, 776 (1954) determined using ferric chloride-sulfuric acid. .

The results obtained are shown in the table below. ·. ■

connection

2
3
V

Lowering of cholesterol
in the blood in%, based on not
treated control animals ■,

5 mg / kg

76
70
68
62

0.3 mg / kg

. 32.
27:

39 ■ ...

no noticeable
reduction

= 3,5-Diiodo-4- {3,5-dimethyl-4-hydroxyphenoxy) -phenethyl alcohol.

= 3,5-Diiodo-4- (3,5-dimethyl-4-methoxy-phenoxy) -phenethyl-

alcohol.

₂ ζ V = comparison compound ("lp-hydroxyphenoxy-S ^ -diiodophenethyl alcohol).

As can be seen from the above results, the compounds of the present invention have 30. Compared to the comparison compound, a considerably superior hypocholesterolemic effect.

Claims (2)

Patent claims: 1. 3,5-Diiodo-4- (3,5-dimethyl-4-hydroxy- or -methoxy-phenoxy) -phenethyl alcohol and derivatives the general formula CH RO in which R and R 'each have a hydrogen atom, each an acetyl group or R a methyl group and R' means a hydrogen atom. 2. Process for the preparation of the compounds according to claim 1, characterized in that one is a compound of the general formula CH in which R is as defined above, is reduced in the presence of an inert solvent at a temperature between -20 and 5O ⁰ C with diborane and optionally the thus obtained phenoxy-phenethyl alcohol acetylated.