DE2048372C - 2,3-dichlorophenoxyacetic acids - Google Patents

Description

-OCH ₁ COOH

or the rest

-CO-

The invention relates to 2,3-dichlorophenoxyacetic acids the general formula

R -

in row the rest

OCH, COOH

-CO-

or the rest

represents, in which R ¹ H ■ - or CH ₃ ■ -, as well as their alkali, piperazine, methylpiperazine and N-methylglucamine salts.

To prepare the compounds according to the invention, one of the esters can be saponified which has the meaning given by condensates of a haloacetic acid ester, in particular of the ethyl chloroacetic acid ester, with a compound of the general formula in which R has. been received i> l. where the ketones required are from the condensation of 2,3-dichloroanisole with 1 unnkh! ..- rid or Thophen-2- b / w. f-Methyl-ihiophen-Z-carboxylic acid chloride in the presence of Altiminiumchl · - rid hen have gone. After saponification ue; The esters produced are those according to the invention; (kr phenoxyacetic acid !! with a strong acid w-. Freedom.

The reaction between the diehloranisole and the: Acid chloride can be found in solvents, ie carbon dioxide. Methylene chloride or without a solvent. The educated methoxyphenylehlorn! can /. B. by the effect of aluminum in a solvent such as benzene οΗ. · ι methylene chloride. be ontmethylierl.

Instead of a haloacetic acid ester with a!); Phenol of the general formula

represents, in which R ^{1 is} Il or CHy-, as well as their alkali. Piperazine-. Methylpipenizine and N-methylglucaniine salts c.

Cl

; - OH

to react can also be a Na- or K-SaI / these phenols, for example with sodium or Ka tium monochlorai. be condensed in aqueous or alcoholic;: medium.

The following examples illustrate the invention. Unless otherwise stated, the Melting points determined in the Koller block.

B e i s ρ i e 1 1

4- (Furanyl-2-keto) -2.3-dichlorophenoxyessinic acid (CE 3598)

a) A solution of 44.2 g of 2,3-dichloroanisole ₄ o. (0.25 mol), 65 g of furoyl chloride (0.5 Moll and 250 ml

Carbon disulfide is replaced in small amounts with 66.6 g of anhydrous aluminum chloride (0.5 mol. During the addition, the temperature is kept at 25 C? !!. Then 5 hours at Room temperature stirred. The mixture is over Left to stand overnight and then heated to 55 ° C. for 1 hour (reflux of carbon disulfide). The solution is cooled and then hydrolyzed with 500 g of crushed ice which concentrated 50 ml Contains hydrochloric acid. The precipitate is separated off and treated with a 30 "solution of sodium hydroxide and then washed with distilled water. 64.7 g of gray crystals are obtained (melting point 148 ° C.). These are recrystallized in methyl ethyl kelon.

57.8 g of crystals (yield 85%) with a melting point of 150 ° C. are obtained.

b) A solution of 40.6 g of the product obtained above in 350 ml of thiophene-freed benzene is mixed in small amounts with 60 g of anhydrous aluminum chloride. The mixture is refluxed for 2 hours and then the solution is hydrolyzed with 400 g of ice. The precipitate is separated, taken up with a 10 ^J Oigen sodium hydroxide solution, and then filled again with the help of 10% IGCR SaIzsäure. In this way 34.8 g of crystals are obtained, which are recrystallized from 200 ml of benzene. 29.1 g of crystals are obtained (yield 75 "...) Which melt at 129 to 130.degree.

L- 1 s a Natnumathylallösuiii 'is formed, iii- <Jc: i! i.5Hu sodium in IHOmI absolute AtInI-all-> hol be histed. Then Id.7 μ phenol ((ι ·: · - ~ NIoI) and then 9. <ig (hloressiiis.iuieä.. ■ - 'ter are poured in. The solution is treated for 14 hours Ui .:: backflow. An> Finally, point II is separated off (separation of the Na'.riumchlorid-.i. I ',. When the Lillral cools down, n crystals are obtained; nl j: ^; ! 15 g of this (yield of crude protein ... '' ¹¹¹ IiI After recrystallization from Isopmpa I. .ihält to 12.9 g i5S "| with a melting point \...! ¹¹ I C.

. ■■ Lies of this ester are in 300 ml of ethyl alcohol I. - >> (dissolved. Add 4 ml of 30% Na- (i: ih> droxid. Ls an abundant white ¹ -.! slaughter is formed. This is 30 minutes under rickllul'i b · . delt. The crystals are washed in uml i \\\\ ν. iLicm alcohol. Then they are dissolved in! 'iii! warm water and the acid is precipitated with i lily \: \ hydrochloric acid. By recrystallizing au, _ir , '; ■! 5H "nigem ethyl alcohol one obtains X.6 g of Kn-> .. iie (bulge 95" »I with a melting point of; - C. The Nairiumsak'can be purified directly by Unikristal - '; ■.: Ren from water C g per 75 ml ^1. ! - scr). Melting point - 260 to 265 C (measure:; .- ek without correction).

B e i s ρ i e 1 2

4-1 rhiophenyl-ketone) -2.3-dichloro-nhenoxy-acetic acid

(CL. 3624) "- ^ ⁰

at line solution of 55 g of 2 3-dichloro-anisole ; ii.3l moles). 91 g of thiophene-2-carbonic acid chloride ■ c. (I2 moli and ISO ml low temperature carbon will gradually Replaced with K2.7 g of anhydrous aluminum chloride, keeping the temperature at about 25 ° C ν. earth. The mixture is 5 hours at room temperature stirred, left to stand overnight and then heated to 55 ° C. for 1 hour. The solution is cooled and hydrolyzed with 250 g E.is and 60 ml concentrated sulfuric acid. The precipitation will treated with a 30% sodium hydroxide solution and then washed with water. After Recrystallization from 95 "ethyl alcohol gives 85.6 g (yield 92% f crystals which at 108 ° C. melt.

It can also be used without a solvent while maintaining the same proportions of reagents or in methylene chloride proceeded, with a solution of 1 mole of dichloroanisole and 1 mole of acid chloride a lighter Excess of powdered aluminum chloride is added.

b) 88.6 g of this ketone (0.30SMoU are in 300 ml of benzene dissolved, 123.5 g of aluminum chloride added in small amounts and then 3 hours brought to the boil internal reflux.

The reaction mixture is then hydrolyzed with 500 g of ice, the precipitate is separated off and mixed with a 10 "/ üigen aqueous Na'.riumhydroxidlösung added. The benzene phase obtained after the hydrolysis is concentrated: an oil is obtained. that on treated in the manner described above; the precipitation is added to the previous one. the Crystals are recrystallized from 50% ethyl alcohol. 60 g of a product are obtained

The reaction can also be carried out in high yield in methylene chloride.

1.1 A solution of ammonium ethylate in 200 ml of abvihitcin ethanol is formed by dissolving 3.45 g of ammonia (i) .l '> Mo!). Then U 1: of the preceding phenol (0.15 mol) and aiisi hli.-I ¹ M-Ii (I. " ¹ XK g (ethyl chloroacetate) are added-ΐΊ.ν, ΓΠ the (ian / e wnd 15 hours under reflux s 'i-la .v.-ü Then, in order to separate the sodium-1.

The ester precipitates out when the liquid has cooled down. Lr is recrystallized i-inii ii a'is isopropaiiol. You get '. ") 4 μ crystals with a melting point of '··>; (.!) Ii. Pure product '. Melts at 63 to 64 C.

This I stci wild in a solution of 300ml ■> 5 "- · ν.ιμυιΐι ethyl alcohol and 9 ml of 10 n-Nairiumhydrnnid k.st. You leave 30 minutes under back-Hu !. '. Cook. The sodium salt precipitate of the acid, which it forms after cooling is separated and taken with warm water. The free acid is then precipitated with the help of a mineral acid. After recrystallization from 50% ethyl alcohol, it has a melting point of 148 to 149'C.

An aqueous sodium phenolate solution can also be used as a starting point. This will be:; n cooking added a slight excess of sodium monochloroacetate and the precipitate formed after Maintaining an alkaline pHA value for 3 hours by refluxing by filtering in the heat severed. The acid is made by adding a strong mineral acid to a hot aqueous solution freed from their salt and extracted in the heat with dichloroethane. After recrystallization an acid which melts at 157 ° C. is obtained from purified dichloroethane.

The sodium salt of the acid melts at 270 C and the potassium salt at 290 C. These melting points, which were determined in the Maquenne block are not corrected.

The addition salt of piperazine (which is formed in ethanol with 2 acid molecules for 1 piperazine molecule is) melts at 216 C. The addition salt of N-methylpiperazine (that from the acid and the base is formed in equimolecular proportions) melts at 140 C. while the addition salt of N-methylglucamine. which was also formed with equimolecular proportions of acid and base, does not crystallize.

Example 3

Proceed in the same way as in Example 1. so you get. starting from 2.3-dichloro-anisole and S-methyl-thiophene ^ -carboxylic acid chloride, the compound CE 3649. which melts at 176 C after recrystallization from 50% ethyl alcohol.

The (hydroxyphenyl) ketone formed as an intermediate in this process melts at 168 ^: C; the phenoxyacetic acid ester melts at 100 C.

1. Acute toxicity

The three compounds became groups of 10 male mice of mean weight of 20 g administered in the usual ways. Mortality was related to intravenous toxicity Determined 24 hours later and, in the case of toxicity per os, 48 hours later. The results are in given in the following table.

Acute toxicity in the mouse

Compound! Oi .. ,, I. V. mg kg mouse: I) L ,,. 1'. C). g U Mau-.

CF 359X j 11th 450 j F? CF 3624! 225 i 1,275 CF 3649 j 5X0 ^! 2.9 tolerance

The compounds were used in doses of 50 to 200 mg per kilogram in the digestive groups given 5 ropes from 3 dogs. The products (T 3598. CT 3624 and CT 3649 do not have any Causing symptom that may suggest some harmful effect.

111. Pharmacology
A. General pharmacology

Apart from the pharmacological effect mentioned in this report, there was no other effect noted.

Both the buccal route and the intravenous route have virtually none of the three connections Effect on the screening tests, with what effects like analgesic. anti-inflammatory, hypoglycated, hypoeholesterolemic. antispasmodic ink, anticholinergic. cardiovascular. psychotropic and other effects can be determined.

In the anesthetized dog, however, the injection of one of these three substances in Do:; s of 10 up to 50 mg / kg a drop in blood pressure in connection with the diuretic effect on the one hand and a on the other hand, this type of molecule has its own effect.

B. Diuretic effect
a) With the mouse

The substances CE 3598, CT 3624 and CTi 3649 have doses from 1 to 50 mg / kg in the case of the first Substance shown a diuretic effect. With the connection CE 3624, for example, the diuresis has decreased doubled at 25 mg / kg, quintupled at 50 mg kg. The effect of the compound CT 3649 is one Quarter of the effect of the compound CF 3624. "

45

55 Bn of the connection c T 359N has in lall cm, ·: intravenous injection in low doses of et λ ,.

1 centigram per kilogram in denersKii l:> Mimic: shown a strong diuretic effect. You> c / v. would take the diuresis is still 2 hours after the in ic ·. tion noticeable, the acme of the effect cherishes / wwchc-15 and 30 minutes. The increase can be f.- ■ 7fold. even the pool of exit diurces cii \

chen. .

In the Fa !! an intraduodenal injection or cn bukkalui administration, the active dose ratio is the same as for administration aiii im ι venous way.

2. In the non-anesthetized dog; After Hu! ·. , tion with 500 ml of physiological water and curing the diuresis for 2 hours, Cl> ■ ·: CT 3649 and CT 3598 was administered buccally in i λ ... from 10 to 100 mg kg. In this way, \ w -.- greatly increased diuresis.

At CT 3624 in a Doms w 20 mg kg hai ··>. the diuresis decreased in 3 hours. The same wai ^; a dose of 10 mg kg is the case. With CF 3 (4 ') the same doses, the diuresis has only decreased. CT 3598 was administered buccally in doses of 50 and 100 mg / kg. The increase in diuresis was present from the first hour in, was noticeable for 3 hours after administration:

The 4- (furanyl - 2 - keto) - 2.3 - dichloro - phen »■ ·.;. acetic acid and its salts as well as the 4 - (ΊΊιίορΙκ:. ·. i-

2 - keto) - 2,3 - dichlorophenoxyacetic acid and,! ■ 4 - (5 - methyl - thiophenyl - 2) - keto - 2.3 - diehi.uphenoxyacetic acid and their salts are used in human therapy as well as in veterinary therapy as diuretics. i especially applicable to all cases that diL Reduce the use of strong diuretics. Their mode of action by inhibiting the Reun-01 Bation of sodium in the proximal tube and the ascending part of the henlctube is in the hydrosodized Reactions and nephrotic edema are of great importance.

These compounds can be used as active ingredients together with other corresponding active ingredients or only in the most important pharmaceutical presentations, such as tablets, coated tablets. Suppositories and injection solutions, to be used.

When administered by the buccal route, the tablets and dragees can be dosed with 0.050 to 1 g.

In the case of injection solutions and suppositories, the dose of active ingredient can be 0.050 to 1 g.

The compounds can be administered in daily doses of 100 to 1500 mg. In these cans they do not cause any secondary disturbing effect. The Kaliflucht in particular is relatively small.

IV. Comparative experiments

b \ By the flound

1. In the case of the 5 - / \ thyl-5- (l-methylbutyO-barbituric acid: (30 mg / kg) anesthetized dog was found to have an extremely potent and early diuretic effect at CE 3624. There were Doses of about 5 to. "0 mg / kg are injected. In most cases, the diuresis has occurred in more than 2 hours tenfold.

The diuretic effect of the compound CE 3624 was similar to that of 4-chloro-N-furfuryl-S-suliamoyl-anthranlic acid (Furosemide) and with that of 2,3 - dichloro - 4 - (2 - methylenebutyryl) phenoxyacetic acid (Ethycric acid) compared.

The studies were carried out with mice in two groups of 6 animals each.

The results obtained are shown in Tables 2 and 3.

"Iabcl! C2 üiuresis in the mouse (2 hours after administration)

CE 3624, mg; kg.
CE 3624, mg kg.

CE 3624. mg kg.

Diuretic activity

Diuresis at
Laboratory animal /
Diuresis at
Comparison animal

Furosemide, mg / kg

Ethacric acid. mg / kg ...

1.20

5.80

5.96

2.60
1.46

compared with
Comparison animals. j

Try after

Student and

Fisher

Cl excretion mEq

(, "- 0.82

N.S.

f ₁₀ = 6.96
u <0.001

f ", = 8.68
a < 0.001

fm = 7.20
iK 0.001

f _{1 (} , = 2.00
NS

»1 * 1

0.248

0.280

0.259

0.519

0.289

S [! I ")

0.026

0.031

0.026

0.016

0.030

Comparison with comparison animals.

Try after

Student and

Fisher

f, "= 1.08

N.S.

f., = 6.73 α <0.001

f>, = 6.99 -κ 0.001

¹ U) - »·

<i < 0.001

t ", = 1.76 N.S.

0.260

0.298

0.276

0.519

0.292

Na excretion 0.019 compared with
Comparison animals.
Try after
Student and
Fisher K excretion m;
m .N \ H compared with
Comparison animals
Try after
Student around
Fisher \ q 0.038 fm = 2.14
NS 0.049 0.006 fm = 0.21
NS 0.029 fm = 6.25
iK 0.001 0.092 0.017 f ", = 3.50
0.001 <
iK 0.01 0.033 fm = 7.22
-κ 0.001 0.073 0.007 U, = 3.89
0.001 <
iK 0.01 0.030 fm = 7.21
iK 0.001 0.064 0.004 tu = 1.73
NS fm = 2.54
0.01 <
u < 0.05 0.054 0.008 N.S.

·) »Ι --_ Average of the separated ions mEq.
· *) Λ, y Ii - mean deviation from m.

Table 3 Diuresis in the mouse (4 hours after administration!

Comparison animals

CE 3624, 200 mg / kg ....

Furosemide, 200 mg / kg ..

Ethacric acid,
mg / kg

Diuretic activity
Volume in ml

IN THE")

1.62

3.27

5.22

4.77

X \ ^! II **)

0.13
0.20

0.22
0.31

Comparison animals.

Try after

Student and

Fisher

fm = 6.97
iK 0.001

I ₁₁ , = 02/14
, / < 0.001

tu, = ° 38
α <0.001

Cl "excretion mEq

0.147
0.437

0.656

0.596

0.016 0.021

0.029

0.038

Comparison animals.

Try after

Student and

Fisher

/, "= 02/11 -κ 0.001

tu, = 15.55 -i <0.001

/ ,,, = 10.88 iK 0.001 Na 'excretion
mEq

0.1 0.485

0.767

0.660 0.020
0.030

0.034

0.042

Comparison animals.

Try after student and

Fisher

fm = 7.96 -κ 0.001

I ₁₁ , = 14.40 u <0.001

fm = 9.97 .κ 0.001

K 'excretion

mEq

0.027 0.080

·>; Ii

0.003 0.006

0.113 i 0.006

0.130

Comparative sticrc.

Try after

Student and

F i s h c r

f, "- 7.02 η <0.001

f, "^ 12.67

η ■ 0.001

0.005 ί /, "- 14.77 -κ 0.001

CO

OO

*) in = average volume.
**) .s / l / ~ ii - deviating uni! from m

9 10

Tables 2 and "S show that the Inventions The compounds are thus erlindungsgcmäßcn

According to compounds, a strong and early strong diuretic with a weakly toxic effect.

have a diuretic effect. They have a strong effect. The toxicity is lower than that of the

Excretion of sodium and chlorine in one only athacric acid and in furosemide.

moderate excretion of potassium. 5

Claims (1)

Claim: - ^ - Diehlorphenoxyessigsäuren the general formula Cl R ~~ f in row the rest Cl