DE1293750B - Unsaturated phenoxyacetic acids and process for their preparation - Google Patents

Description

1 2

The invention relates to new [4- (2'-methylenalka- are, which result from excessive retention of

noyl) -phenoxy] -acetic acids, compounds which produce electrolytes, and a process for their

diuretic, natriuretic and chloruretic in-house production.

Own shafts and therefore for the treatment of many objects of the invention are compounds

Diseases such as hypertension and edema are useful 5 of the general formula

X X

in which R is a QHs- or CH ₂ - CF3 group and each X is a CH: s group or the two substituents X together are the

- CH = CH - CH = CH group

mean, and a process for the preparation of these compounds, which is characterized in that one a compound of the formula

X X

in which R and X have the significance indicated above ₃₀ are agile, to ensure complete reaction

and Y have a hydrolyzable carbon feed.

acid ester-, carbamoyl-, N-mono- or di-substituted- Preferably a [4- (2'-methylenalkanoyl) -carbamoyl- or cyano group, in per se phenoxy] acetamide, ester or acetonitrile in counter-known Way hydrolyzed. ■ Was hydrolyzed by a weak base.

If Y is a hydrolyzable carboxylic acid ester 35 The reaction mixture is then treated with an organic

means group, the hydrocarbon part of which can be niche or inorganic acid, for example

for example alkyl, alkenyl, cycloalkyl, cyclo-hydrochloric acid, added.

alkenyl, aryl, aralkyl, such as methyl, ethyl, propyl, The ver-pentyl for the process according to the invention, Hexyl, allyl, 2-butenyl, cyclopentyl, cyclopentene ester, amide and nitrile starting materials hexyl, 4-methylcyclohexyl, cyclopentenyl, cyclo- 40 can be herhexenyl by conventional methods, Phenyl, p-tolyl, benzyl or phenylethyl, for example by reacting an alkali. When Y is an N-mono- or di-substituted carb salt, such as the sodium or potassium salt of a Amoyl group, the substituent or substituents can 4- (2'-methylenalkanoyl) phenol with a 2-bromotuent the above-mentioned organic acetamide, an ester of bromoacetic acid or with Be radicals or together with the nitrogen atom 45 chloroacetonitrile.

a heterocyclic radical, for example pyrroli- The sodium and potassium salts of 4- (2'-methy-

dino- (l), piperidino or morpholino, important alkanoyl) -phenols can be derived from their

th. speaking 4- (2'-methylenalkanoyl) phenol precursors

Hydrolysis can be synthesized in water alone, precursors by combining them with a

preferably with movement, carry out, or one treats 50 sodium or potassium alkoxide. The 4- (2'-Me-

can use organic solvents. It would be thylenalkanoyl) phenol starting materials

However, found that the implementation is most advantageous- prepared by various processes, for example

most adherent using organic solutions from the corresponding Mannich compounds

medium expires, and for this reason one gets fertilize which itself by implementing a

particularly good results when using ethanol. 55 alkanoylphenols with formaldehyde or paraform

It was also found that the hydrolysis of both aldehyde and the acid addition salt of a secondary

in weakly basic solutions as well as in solutions amine, for example the acid addition salt of a

takes place that contain small amounts of acid, dialkylamine or piperidine or morpholine,

for example in a 5% sulfuric acid solution. getting produced. The Mannich-

Most advantageously, however, the reaction takes place in 60 amines are then carried out directly, for example

Presence of a weak base; from this heating to temperatures above room temperature

Basically one prefers an aqueous solution of temperature, to the corresponding 4- (2'-methylenalkanoyl) -

Sodium bicarbonate. Temperatures and translation phenol derivatives decomposed. This implementation leads

times are not critical; it has been found that it is most advantageous in the presence of a solution

the method by means of room temperature or below 65, which has a high dielectric constant

Warming, for example on a steam bath, has, for example, dimethylformamide. Usual-

can be carried out; the procedure is wise, however, one treats the salt of Mannich-

one within such periods of time by the not amines with a weak base, for example

Sodium bicarbonate to obtain the corresponding Mannich base which is then decomposed to the desired 4- (2'-methylenealkanoyl) phenol. Some of the Mannich bases decompose at room temperatures, but generally the decomposition is effected by heating. It has been found that it is sometimes advantageous to treat the Mannich base with a suitable quaternizing agent, for example an alkyl halide, to produce the corresponding quaternary ammonium salt. This quaternary salt is then treated with a base, for example an aqueous solution of sodium bicarbonate. Following the so occurred decomposition treating the obtained product to produce the desired ₅ 4- (2'-Methylenalkanoyl) phenol with a suitable acid, for example hydrochloric acid.

Another process for the preparation of the 4- (2-methylenalkanoyl) phenols consists in that one alkanoylphenol with a suitable halogenating agent, such as chlorine, bromine or iodine monochloride, and then the 4- (2'-haloalkanoyl) phenol thus prepared with agents that split off hydrogen halide, such as tertiary amines, metal halides, Alkali acetates and alkali carbonates. Triethylamine, anhydrous lithium chloride, lithium bromide, Silver acetate, potassium acetate, silver fluoride, and potassium carbonate are particularly effective Agents that split off hydrogen halide. Examples of halogenating agents are chlorine and bromine or iodine monochloride in question. In general, the elimination of hydrogen halide can be carried out in any inert solvent in which the 4- (2'-haloalkanoyl) phenol and the hydrogen halide release agents are reasonably soluble; Dimethylformamide has proven to be proved to be a particularly suitable medium for carrying out the reaction, especially if the Hydrogen halide is lithium chloride or lithium bromide.

The reaction temperature and the reaction time are not particularly critical, and the person skilled in the art can generally vary the temperature to achieve the desired rate of reaction receives.

To make the alkanoylphenol reactants According to the Friedel-Crafts reaction, a suitable phenol ether, for example an anisole or phenetol, reacted with an alkanoyl halide in the presence of a metal halide and the etherified alkanophenone intermediate thus prepared is then converted into the desired one Alkanoylphenol are hydrolyzed. Suitable metal halides include, for example, anhydrous Aluminum chloride. Often the Friedel-Crafts reaction gives a mixture of the 2- and 4-isomers the alkanoyl phenol ether reactant; this is particularly the case when the Phenol ethers used as starting material contain a substituent in the 3-position of the benzene nucleus, for example when the phenolic ether reactant is 3-methyl anisole. Such a mixture of isomers is hydrolyzed. The isomeric alkanoylphenol compounds thus prepared are then easily separated by distillation.

The alkanoylphenol starting material can also be prepared by means of the Fries rearrangement, which consists in treating a phenol with an alkanoyl halide to produce the corresponding Manufacture phenol esters; then heated the ester with aluminum chloride to a To effect rearrangement on the core, thereby producing the desired substituted alkanoyl phenol. This method is most suitable for the preparation of the 2-alkanoylphenol isomer but also under suitable conditions for the preparation of the 4-alkanoylphenol isomer.

Yet another process for the preparation of the alkanoylphenols as starting materials is based on the Reaction of a Grignard reagent with an appropriate formyl-substituted phenol ether in which the ether residue is a lower alkyl group, e.g. B. methyl or ethyl. The one produced in this way, with Alkoxy substituted benzyl alcohol intermediate is then oxidized to the corresponding ketone derivative and splits off the ether group by conventional means. Suitable oxidizing agents are for example sodium dichromate dihydrate.

The 4- (2'-methylenalkanoyl) phenols are generally obtained in the form of crystalline solids, which one optionally by recrystallization from a suitable solvent, for example Hexane or a mixture of hexane and benzene.

Pharmacological examinations of the products according to the invention showed that they are excretory of more electrolyte than can be achieved by known diuretic agents can; although most known diuretics reach a threshold or limit value in the amount of electrolyte which they can cause excretion, but the compounds according to of the invention require a considerable increase in this limit value.

The diuretic effectiveness of the compounds obtainable according to the invention was compared with that of a connection according to the published documents of Belgian patent 612 755 compared.

The experiments were carried out as follows: Mixed breed dogs were trained in the post-absorptive state, 500 ml of water are administered orally and 3.0 g of creatinine are administered subcutaneously. One Infusion of an isotonic phosphate buffer containing mannitol was given in an amount of 3.0 ml / Min. Administered, after 20 minutes the bladder was emptied with a catheter, then the Repeated emptying at intervals of 10 minutes. In the middle between two evacuations was venous blood taken.

After this control phase, the substance to be examined was administered intravenously in an initial dose of 2.5 mg / kg ^ injected. After that, the dogs received the compound to be tested as an infusion at a rate of 3.0 mg / kg / hour.

After 20 minutes for equilibrium to be established, urine was drawn and the Urine sampling repeated every 10 minutes. In the middle between two urine samples venous blood was drawn.

The increase in the excretion of sodium, potassium and chloride ions caused by the compound is given in the table below. The increase in excretion in bitches is displayed in microequivalents per minute for the specified dose levels.

5 link Na ⁺ - Disc clothing
C.
0
• si K "
see the end
manure cr-
shit 6th Excellent
River
m divorced
> ity-
tight. effectiveness C ¹ ) D-C ii C.
D. D-C D. the end
manure Cl ³ ) D ₁ -C ₁ Example 7 of the invention D-C o / 3 C ₂ H ₅ -CC- ^ VO-CH ₂ -COOH
3
1019 1006 99.8 13th 76 4th 4.3
10.6 6.3 very
effective Il
CH ₂ 1131 1127 [4- (2'-methylenebutyryl) -l-naphthyloxy] acetic acid Example 10 of the invention _o H ₃ C CH ₃ CF ₃ CH ₂ C - C - \ ~ _y - O - CH ₂ - COOH 49 1430 99.48 63
131 68 2.6 10.1 very H
CH ₂ 1479 8.5
1608 1599.5 12.7 effective 2,3-dimethyl-4- (2'-methylene-4 ', 4', 4'-trifluorobutyryl) -
phenoxy acetic acid Documentation of the Belgian patent 612755 O
I! Il xi — v
C ₂ H ₅ -CC- ^ ^ -Q-CH ₂ -COOH 3 99.7 13th
"27" 14th 0.9 CH ₂ 35
~ 38 ~ 35 2.1 practically
ineffective 4- (2'-methylenebutyryl) phenoxy acetic acid

') Increase in excretion caused by administration of the control compound (microequivalents / min.).

² ) Increase in excretion caused by administration of the compound to be investigated (microequivalents / min.).

³ J Increase in excretion caused by administration of the control compound (ml min.).

*) Increase in excretion caused by administration of the compound to be investigated (ml min.).

The test results show that the compounds according to the invention are very effective, while the connection is made according to the published documents of Belgian patent 612 755 is practically ineffective.

example 1

[2,3 - Dimethyl -4- (T- methylenebutyryl) phenoxy] acetamide is dissolved in ethanol and treated with an aqueous sodium bicarbonate solution. The solution is heated on a steam bath with stirring for 2 hours. The reaction mixture is then concentrated to dryness under reduced pressure. The white, solid residue is extracted with warm water and filtered. The aqueous filtrate is acidified to Congo red paper by adding 6η hydrochloric acid, and the resulting oil is extracted with ether, and the combined ether extracts are dried over anhydrous magnesium sulfate. The ether is evaporated off under reduced pressure and the residue is extracted with boiling methylcyclohexane. The solution is treated with activated charcoal to decolorize, filtered and cooled. This gives [2,3-dimethyl-4- (2'-methylenebutyryl) phenoxy] acetic acid. Their melting point after purification by recrystallization is 83.5 to 84.5%.

Example 2

Following the procedure of Example 1, [4 - (T - methylenebutyryl) - naphthyloxy - (1)] - acetamide [4- (2'-methylenebutyryl) naphthyloxy (1)] acetic acid is prepared. After purification by recrystallization, their melting point is 106 to 109 ° C.

Example 3

In the manner described in Example 1, [2,3-dimethyl-4- (2'-methylene-4'-4'-4'-trifluoro - butyryl) - phenoxy] - acetamide [2,3 - dimethyl-4- (2'-methylene-4'-4'-4'-trifluoro-butyryl) -phenoxy] - acetic acid, which melts at 82 to 84 ° C after cleaning by recrystallization.

The starting materials used for the above Examples 1 to 3 are according to the above described methods by reacting an alkali salt of a suitable 4- (2'-alkylidenalkanoyl) phenol made with 2-bromoacetamide.

Claims (2)

Patent claims:
1. Compounds of the formula
XX R-C- Il CH ₂ O- O
L ₂ -COH in which R is a C2H5 or CHo - CFs group and each X is a CHs group or both Substituents X together the - CH = CH - CH == CH group
mean. 2. Process for the preparation of the compounds according to claim 1, characterized in that one a compound of the formula O ^XX R - C - C - ^ y ~ O - CH ₂ -Y
CH ₂ in which R and X are those specified in claim 1 an- io N-mono- or disubstituted carbamoyl or cyano Have meanings and Y means a hydro group, in a manner known per se lysable carboxylic acid ester, carbamoyl, hydrolyzed.