DE1618716C - Square brackets on 2,3, dichloro 4 (2 methylenbutyryl) phenoxy Square brackets on fluoroacetic acid and its pharmacologically acceptable salts and process for the preparation of these compounds - Google Patents

Description

The invention relates to [2.3 dich'.or-4- (2-methylenebutyryl) -phenox \] -fluoroacetic acid and their pharmacologically acceptable salts and a process for the preparation of these compounds, the is characterized by it. that in a known manner 2-methylene-2'.3 ■ -dichlor-4 ■ -hydroxybutyrophenone with ethyl bromofluoroacetate in the presence of a base, then the so formed [2.3 - dichloro - 4 - (2 - methylenebutyryl) phenoxy] - fluoroacetic acid ether in known per se Way hydrolyzed and the acid D5 obtained, optionally in a manner known per se in a transferred pharmacologically acceptable salt.

[2,3-dichloro-4- (2-methylenebutyl) phenoxy] fluoroacetic acid has the following structural formula:

40

C ₂ H ₅ -C-CO - <
CH ₂

CHF-COOH

45

The 2-methylene-2 ', 3'-dichloro used as starting compound in the process according to the invention - 4 '- hydroxy - butyrophenone and its production are in the German Offenlegungsschrift 1 543 185.

The hydrolysis of the present invention can be carried out with the aid of an acid such as hydrochloric acid will.

The salts according to the invention can be with the help of bases, such as alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates and the like. Suitable bases are, for example, sodium bicarbonate, Sodium hydroxide, potassium carbonate, potassium hydroxide and calcium hydroxide.

The salts according to the invention are generally obtained as crystalline solids and can optionally by recrystallization from a suitable solvent such as water or a mixture of water and a lower alkanol.

example

Production of sodium [2,3-dichloro-4- (2-methylene " butyryU-phenoxyJ-fluoracetate

Level a

Ethyl [2.3-dichloro-4- (2-methylenebutyryl) phenoxy] fluoroacetate

To a solution of 4.90 g (0.02 mol) of 2-methylenebutyryl - 2'.3 '- dichloro - 4' - hydroxy - butyrophenone (I) in 20 ml of dimethylformamide are 6.08 g (0.044 mol) Given potassium carbonate. Then 8.14 g (0.044 mol) of ethyl bromofluoroacetate are added ^ and the reaction mixture is heated to 55 to 60 "C for 30 minutes with stirring.

The cooled reaction mixture is with ^ l ml Water treated. and the oil that forms becomes with Ether extracted. The combined extracts are ii dried over anhydrous magnesium sulfate, and the ether is evaporated under reduced pressure. the ethyl ester of [J.3-dichloro-4- (2-methy! enbutyryllphenoxy] - Fluoroacetic acid remains in the form of an oil.

Level B.

[2.3-dichloro-4- (2-methylenebutyryl) phenGxy] fluoroacetic acid

The ester obtained in stage A is dissolved in 75 ml of ethanol and treated with a solution of 3.36 l> (0.04 mol) of sodium bicarbonate in 150 ml of water. The mixture is heated on a steam bath with stirring for 15 minutes and then concentrated under reduced pressure to a volume of 50 ml. 50 ml of water are added to the residue, and the solution is made acidic against Congo red paper by adding 6N hydrochloric acid. The oil that forms is extracted with ether and the combined extracts are dried over anhydrous magnesium sulfate. The ether is evaporated off under reduced pressure, resulting in 6.42 g (100%. Based on I. cf. stage A) of an oily residue which is known as [2,3-dichloro-4- (2-methylenebutyryl) phenoxy] - fluoroacetic acid is identified. [KMR spectrum (CDCl ₁ ) Λ = 1.13 (3 H. t = CH ₃ ), 2.48 (2 H, q = CH ₂ ), 5.68 (1 M, s = CH). 6.05 (1 H. s = CH), 6.10 (1 H. d = CHF-), 7.23 (2 H, S = ArH). 11.03 (IH. S = COOH); FR spectrum (KBr) 1770 (COOH ,,! 670 (C = O), 1585 (C = C) Cm " ¹ ].

Level C

Sodium [2,3-dichloro-4- (2-methylenebulyryl) phenoxy] fluoroacetate

[2.3-Dichloro-4- (2-methylenebutyryl) -phenoxy] -fluoroacetic acid of step B is in a boiling solution of 1.68 g (0.02 mol) of sodium bicarbonate in Dissolve 50 ml of water, and the pH is adjusted by adding several drops of a 20% aqueous sodium hydroxide solution set only 7.5 to 8.0. The boiling solution is then quickly put in an ice bath cooled, whereby 4.71 g (69%, based on I, cf. Stage A), sodium [2,3-dichloro-4- (2-methylenebutyryl) -phenoxy] -fluoroacetate deposit in the form of a white, crystalline solid. This salt can go through Recrystallize from boiling water to be further purified and has a m.p. = 143 to 144 ° C (Dec.) On.

Analysis for C _n H ₁₀ Cl ₂ FNaO ₄ :

Calculated ... C45.50. H 2.94. Cl 20. <S7. F 5.54% found ... C 45.43, H 3.25. Cl 20 54. F 5.45%. '

The compounds according to the invention are effective diuretic and saluretic agents used in the Treatment of \ pathological conditions can be used with electrolyte and fluid retention as well as are linked to hypertension. When used in therapeutic dosages in conventional When administered to vehicles, they are effective in reducing the amount of sodium and chloride in the blood in the body, dangerous excesses decrease Fluid levels to acceptable levels and generally relieve those commonly associated with edema pathological conditions,

The products according to the invention can be used in one large quantities of therapeutic dosages in conventional carriers are administered, for example by oral administration in the form of a capsule or tablet, as well as by intravenous injection. The dosage of the products can also vary within a wide range, for example in form of capsules or tablets containing ν λπ 5 to about 500mg active ingredient for this symptomatic classification the dosage on the patient to be treated. These dosages are well below the toxic or lethal dose of the products.

A suitable unit dosage form of the invention Products can be made by adding 50 mg of the product with 144 mg of lactose and 6 mg magnesium stearate mix and the 200 mg mix in a # 3 gelatin capsule. In the same way, by using more active ingredient and less lactose put other dosage forms in # 3 gelatin capsules will. Compressed tablets. Pills or other desired unit dosages can be made up by incorporating the compounds according to the invention by customary methods, and If appropriate, the compounds according to the invention can be prepared by methods known to pharmacists be prepared as elixirs or injectable solutions.

The diuretic activity of the compound according to the invention sodium [2,3-dichloro-4- (2-methylenebutyryU-phenoxy] -fluoroacetate (l) has been identified with the diuretic potency of the compounds 2,3 - dichloro - 4 - (2 - methylenebutyryl) - phenoxyacetic acid! 2), 3-chloro-4- (2-phenylacryloyl) -phenoxyacetic acid ^) and [3-chloro-4- (2-methylenebutyryl) phenoxy] acetic acid (4) compared. These were carried out the following experiments:

I. Intravenous trials

Trained mixed breed dogs in the post-absorptive stage are given 500 ml of water and subcutaneously 3.0 g creatinine administered. It will be an infusion of isotonic phosphate buffer that contains mannitol.

with a. Speed of 3.0 ml / min, given, After 20 minutes, the urinary bladder is emptied using a catheter, and then every 10 minutes repeatedly collected urine. Samples are taken in the middle between two urine samples taken from venous blood. After this control phase, the substance to be tested is given a basic dose Injected intravenously and additional material added to the infusion in the amounts indicated. To a period of 20 minutes to adjust the equilibrium Aird to repeated times in Urine and blood were collected at 10 minute intervals.

II. Stationary experiment

No infusion dose is administered here, instead the substance to be tested is used after the control phase Injected intravenously as a single dose, and after a period of 15 minutes for cessation serial urine and blood samples are taken to maintain equilibrium.

The increase in the excretion of sodium, potassium and chloride ions caused by each compound

Elimination is given in the table below. The increase in excretion is expressed in microequivalents specified per minute at the stated dosage levels.

The test results show the superiority of the compound (1) according to the invention over the prior art compounds (2).

Recognize (3) and (4) in diuretic effectiveness.

connection

"T

Connection (1):
according to the invention

OCHCO, Well

Connection (2):

2,3-dichloro-4- (2-methylenebutyry]) phenoxyacetic acid

Starting dose Infusions
dose
mg ^ g, h 2.5 mg kg 3.0 1 mg
stationary 2.5 mg / kg 3.0

N / A*

JL
1262

21
1746

8th
1369

Reabsorption

99.9_
83.8

99.9
83.0

K ' Cl Out
divorced
Liquid
amounts C.
η c_
D. 9 5 3 95 1296 11th 6th 11th 1 92 1704 14th 9 3 0.4 106 1239 10.7

C = increase in excretion caused by administration of the control compound.

D = increase in excretion caused by administration of the compound to be investigated.

continuation

X'erhinduri'j

Connection length i3): j 6.25mg kg;

3-chloro- '2-phenyIacryioyII-phenoxy- j i

acetic acid I j

Connection (4): j 2.5 irm. k «!

[3-Ch! Or-4 - (? - methylenbutyry!) - j j

pheno. <v] acetic acid! j

* l (- hrhohung of excretion, which is bei.irkt by administration of k.omroll> Getting Connected DI rhohung the Ausscheidung- the i.ibe by (the / u uniersuchenden connection bewirk is!

Claims (3)

Palent claims: 1. [2.3 - Dichloro -4 - (2 - methylenebutyryl) phenoxy] fluoroacetic acid and their pharmacologically acceptable salts. 2. A method for producing the compounds according to claim 1, characterized in that one in a conventional manner 2-methylene-2'.y - dichloro ■ 4 '- hydroxy - butyrophenone with ethyl bromofluoroacetate in the presence of a Reacts base, then the so formed [2.3 - dichloro - 4 - (2 - methylenebutyryl) - phenoxy] -fluoroacetic acid ethyl ester hydrolyzed in a manner known per se and the acid obtained optionally in a manner known per se in a transferred pharmacologically acceptable salt. 3. Diuretic. containing compound according to claim 1.