DE1935344C - p chlorine or p bromine phenoxyisobut acid ester and drugs containing it - Google Patents

Description

Y
/
- N group

\
Y '

means in which Y stands for a hydrogen atom or an alkyl group with up to 3 carbon atoms and Y 'represents an alkyl group of up to 3 carbon atoms or a cyclohexyl group and Y and Y 'together with the nitrogen atom can form a morpholino group.

2. Medicament, characterized by a Geh ilt on a compound according to claim 1.

The present invention relates to new p-chloro- or p-bromo-phenoxyisobutyric acid esters with cholesterol The general formula maintains the blood-diminishing properties

CH ₃
O - C - CO - OCH ₂ CH ₂ CH ₂ - COR

- N group

Y '

means in which Y represents a hydrogen atom or a Alkyl group with up to 3 carbon atoms and Y 'for an alkyl group with up to 3 carbon atoms or a cyclohexyl group and Y and Y 'together with the nitrogen atom form a morpholino group can form.

The following radicals R can be mentioned, for example: methoxy-. Ethoxy. Propoxy, benzyloxy, methylamine, Ethylamino, isopropylamino. Cyclohexylamino-. Dimethylamine, diethylamino, dipropylamino, morpholino groups. The substituent X can a chlorine or bromine atom sdn.

The invention also relates to medicaments which contain the p-chloro or p-bromine-phoxviso-butter acid esters according to the invention contain.

The esters and amides of the formula given above can be obtained by processes known per se will. A simple method of making the esters is that the potassium salt of a 4-haloeenphenoxyisobutyric acid with an alky- or aralkyl 4-halobutyrate in a solvent condensed of a high boiling point and in the presence of potassium iodide. For the production of aer Amide can be an acid halide of the 4-halo

, o phenoxyisobutyric acid on an N-substituted 4-hydroxybutyramide, that according to the general method of Re ρ pe. Liebig's Annals of Chemistry 596, 19d. \ 188 to 2 "> 8 has been established Another useful method is that

ts one transesterification of the lower alkyl esters of the "4-halophenoxyisobutyric acids by the same -4-hydroxybutyramides causes.

The following examples, in which parts indicated are based on weight, unless

, o this is indicated differently in individual cases. explain such procedures. The compounds prepared in this way have not yet been written down in the literature.

B e i s η i e 1 1

4'-chlorophenoxy-isobutyric acid ester
of 3-ethoxycarbonylpropyl alcohol

100 parts of dry potassium 4'-chlorophenoxyisobutyrate are left with 39 parts of ethyl 4-chlorobutyrate

in the presence of 3 parts of potassium iodide in 100 volume

share ~ dry dimethylformamide react. The mixture is heated to 155 ° C. for 24 hours while stirring Treating with water and extraction with ether, the ethereal solution is dried and evaporated.

The product you are looking for fills in solid form. It will

recrystallized from isooctane. Yield 65%. It is a white solid having a melting point of 43 ⁰ C (Maquenne). which is soluble in ether and lipoids and insoluble in water.

CH ₃

in which X is a chlorine or bromine atom and R is a Alkoxy group with up to 3 carbon atoms, a benzyloxy or a

Analysis for the gross formula C ₁₁₁ H ₂₁ ClO ₅ :

Calculated ... C 58.44. H 6.43. Cl 10.79%;
found .... C 58.76, H 6.18. Cl 10.78%.

Example 2

4'-B.omphenoxyisobutyric acid ester
of 3-ethoxycarbonylpropyl alcohol

The procedure is as in Example 1, but using 100 parts of potassium -4'-bromophenoxyisobulyrate and

35 parts of ethyl 4-chlorobutyrate. 65 parts of the desired product are obtained (yield 70%). that from isooctane is crystallized out. Melting point (maquenne) 42 C.

Analysis for the gross formula C ₁₁₁ H ₂₁ BrC) ₅ :

Calculated ... C 51.22. H 5.67. Br 21.40%:
found .... C 51.38, H 5.29. Br 21.40 ", ..

B c i s ρ i e 1 3

4'-chlorophenoxyisobutylcrs; iiireestcr
of 3-benzyloxycarbonylpropyl alcohol

The procedure is as in Example 1, but using 67 parts of potassium -4'-chlorophenoxyisobutyrate and

36 parts of BcnzyM-chlorbulynii in 50 parts by volume Dimethylformamide and in the presence of 2.3 parts Potassium iodide. You get 38 parts of the wanted one

Product (yield 57%). The crystallization is effected η an isooctane-ethyl ether mixture, melting point 37 C.

Analysis for the gross formula C ₂₁ H ₂₃ ClO ₅ :

Calculated ... C 64.52. H 5.94. Cl 9.10%:
found C 64.90. H 5.53. Cl 9.23%

Example 4

4'-chlorophenoxyisobutters: iureester
of S-IN-isopropyl-aminocarbonyli-propyl alcohol

A :: ulamm: The mixture is stirred at 41 OC parts 4'-C'hlorphenoxyisobuuersäurechlorid in the solution of 28 parts of 4-hydroxy-N-isopropylbutyramid in 300 parts by volume of Te'.riihydrofuran in the presence of 18.4 parts of ^tri-. The mixture is kept in scrambled eggs for 12 hours at room temperature, filtered, and the triethamine chlorohydrate obtained is mixed with rhodium. Then the solution is concentrated until an oil is formed which crystallizes . Parts of the sought product are obtained (yield 60%). It ■ • ■ ..al from ΛΐΐηHither umknstallisien. Melting point \\ aquenne) 71 C.

■■ -. ■ .ιal \ se for the BruHolormel C ₁ -H ₂₄ ClNO ₄ :

1.! - calculates ... C 59.73. 117.07. N 4.09 ",.;
found C 59.92. H 7.22. N 3.72 "».

B e i s ρ i c '5

4'-chloropliene oxyisubutate
of 3-1N-cyclohexylaminocarbcinyll-propyl alcohol

Man \ ^r he ..hrt as used in Example 4 but 33.4 [hasten 4-1 lydroxy-N-cyclohcxvlbuUiamid. To give 3 ⁷ parts (60% yield) of the desired product, which is recrystallized from lsopropyläthcr. Melting point (maquenne) 59 C.

Analysis for the gross formula C ₂₁₁ H, _S C1NO ₄ :

1-rrechnel ... C 62.90. H 7.38. N 3.66%:
found .... C 63.20. H 6.95. N 3.35%.

Example 6

4'-bromophenoxy isobutyrate
of 3- (N-cyclohexyl-aminocarbonyl) -propyl alcohol

The procedure is as in Example 4, using over 49 parts of 4'-bromophenoxyisobutyryl chloride and 33.4 parts of 4-hydroxy-N-cyclohexylbutyramide. 42 parts (yield 61%) of the desired product are obtained. Jas is recrystallized from isooctane. Melting point 78 C.

Analysis for the gross formula C ₂₀ H ₂₈ BrNO ₄ :

Calculated ... C 56.27. H 6.56, N 3.29%;
rounded .... C 56.44, H 6.45, N 3.32%.

Example 7

4'-chlorophenoxy isobutyrate
of 3-morpholinocarbonylpropyl alcohol

48.5 parts of ethyl 4'-chlorophynoxyisobutyrate are dissolved. that according to the procedure of Juli a (Bull. Soc. (. "him. France (1956), 776 to 783) in 200 parts by volume of dry toluene in (ii.cnwart of 34.5 parts of 4'-hydroxybutyrylmornholine and 2 parts of aluminum isopropoxide. The mixture is heated for 8 hours, the azeotropic toluene-ethanol mixture collects. The volatile products are filtered and distilled, whereby the temperature is raised to 200 ° C / Heated 0.2 torr. The sought product crystallizes on cooling and is recrystallized from isopropyl ether. Melting point (maquenne) 66 ° C.

Analysis door the gross formula C ₁₈ H ₂₄ ClNO ₅ :

Calculated ... C 58.46, H 7.79, N 3.79%;
ίο found .... C 58.22, H 7.61, N 3.57%.

Example 8

4'-chlorophenoxy isobutyrate

of 3- (dimethylaminocarbonyl) propyl alcohol

In a vessel with a mechanical agitator and protection against moisture, one slowly introduces, keeping the temperature at 0 ° C. 55 parts of 4-chlorophenoxyisobutyric acid chloride in 30 parts 4-hydroxy-N.N-dimethylbutyramide. solved in 360 parts by volume dry tetrahydrofuran in the presence of ^ I parts of triethylamine. The temperature is left rise and stir for 2 hours at room temperature. The triethylamine chlorohydrate formed is filtered off and washes with tetrahydrofuran. The filtrate is concentrated by distillation under vacuum and the oil obtained is distilled. 51 parts of 4'-chlorophenoxyisobutyrate of? - (Dimethylaminocarbony (propanol as a thick, pale yellow liquid with a boiling point of 192 C'0.8 Torr.

A rectification yields a product with a boiling point of 200 to 202 C 1 Torr, its purity according to gas chromatography over 99%. Exploitation. 68%.

Elemental analysis for C _U , H ₂₂ NO ₄ C1:

Calculated ... C 58.6. " ^1. H C V. N 4.27%;
found .... C 58.25, H 6.31, N 4.66%.

The 4-hydroxy-N, N-dimethylbutyramide used in this example is used according to the procedure by R ep pe. (Liebigs Annalen der Chemie, 596, 1955, 188 to 228) by condensation of - / - butyrolactone prepared with dimethylamine in the following way: in a vessel with a stirrer and reflux condenser 100 parts of dimethylamine and 94 parts of γ-butyrolactone, dissolved in 360 parts by volume, are introduced absolute ethyl alcohol. The reaction is exothermic and the temperature should be increased by cooling be kept low. The reaction mixture is then left to stand at room temperature for one night, then heated under reflux for 8 hours. Distillation makes the alcohol at atmospheric Pressure removed and the amide distilled under vacuum. A colorless liquid with a boiling point is obtained of 135 ° C lTorr (or 170 ° C / 20Torr). Receive: 129 pieces. Yield 91%.

Example 9

4'-chlorophynoxyisobutyric acid ester
des .VfDimethylaminocarbonyO-propyl alcohol

Dissolve 48.5 parts of ethyl-4'-chlorphenoxyisobulyrat in 200 parts by volume of dry toluene in the presence of 26.2 parts of 4-1-lydroxy iM.N-dimethyl- (i bulyramid ₅ and 2 parts of aluminum isopropylate. The mixture is heated 8 hours , wherein the azeotropic mixture of toluene and ethanol is collected in a vessel with a distillation column

controllable reflux is equipped. It is then filtered, the solvent evaporated in vacuo and the residue distilled. An almost colorless, slightly yellow oil with a purity of 99.5% is obtained after chromatography in the gas phase. Boiling point 175 ^c C / O, l torr. "

This oil is hypothermic at room temperature on. Crystallization occurs by cooling or by seeding with crystals of the product receive. The melting point is 34 ° C (suddenly occurring above the Maquenne block).

The product can be recrystallized. For this purpose, for example, it dissolves at room temperature in petroleum ether, ethyl ether or isopropyl ether and cool this solution with stirring to about - 50 ⁰ C. were obtained in this way, after drying under vacuum sulfuric acid-white needles with a very high purity.

Analysis for the gross formula C ₁₆ H ₂₂ NO ₄ Cl:
Calculated:

C 58.62, H 6.77, N 4.27, Cl 10.85%;
found:
C 58.62, H 6.47. N 4.37. Cl 10.60%.

If you add some needles of this product to the im oily liquid obtained in the first paragraph of Example 8 or if this liquid is cooled below the specified Conditions, this is how the crystallization is also effected.

Toxicological properties

The products of the above general Formula were administered orally to "Swiss albino" mice. Under these conditions were received the following lethal doses per kilogram of animal weight:

R. carrier ■ ■ - - -
LD ^ ₀ mg / kg Procedure according to L itc li
fe I d and W i 1 c 0 χ 0 η b) X Method according to Reed and P = 0.05 Isopropylamino 10% resin solution M u e η c h al 2450 <
<4750 Cl Cyclohexylamino the same about 3220 3350 < Cl about 3565 <6800 Ethoxy the same 2900 < Br about 3810 <4300 Ethoxy the same - Cl Benzyloxy the same > 5100 2500 < Cl about 3580 <4650

Ί Ann. J. Hsu. 27,493.

"l J. Pharm. Expll Terap. 96, 99.

Symptoms of toxic doses occurring within 2 hours of product administration are Spasmophilia. Bradypnea and cyanosis.

4'-chlorophenoxyisobutyrate of 3- (dimethylaminocarbonyl) -pro ~ anol has. Orally administered to "Swiss albino" mice, a non-toxic maximum dose of 1 ig leg animal weight. The LD ₅₀ is 1.90 g kg animal weight and the LD ₁₀₀ 3 g kg animal weight.

Pharmacological properties

The effectiveness of the products according to the invention in reducing the cholesterol content of the blood in rats "Sprague Dawley" (male animals weighing 200 to 250 g) determined. This Rats were fed normal diets and product administration was determined. The rats were treated orally daily at doses of 100 and 400 mg per kilogram of animal weight, with the

4c product in a mixture of 10% gum arabic was suspended.

The cholesterol content was determined by the method of Watson (Chlin. Chim. Acta, 1960, 5, 637), which makes it possible to determine the cholesterol from 20 a \ serum or plasma without deproteinization.

In this way, the following results are obtained. Designated in the various tables XTE the mean cholesterol value of the group of K ^ niroll animals, XTR the mean cholesterol value d 'τ group of treated animals, where the sign + a significant and + + a see; indicates significant difference.

Cholesterol levels before and then 1 week after

a) 4-chlorophenoxyisobutyrate of N-isopropylo-aminocarbonylpropyl alcohol

product

Control (gum arabic solution).

Product according to the invention

100 mg / kg

400 mg / kg.

Who! of the cholcsterin Medium difference content g / l serum XTE - XTR 0.79 (0.58 to 1.03) 0.56 0.23+ + (0.45 to 0.66) 0.38 0.41 ++ (0.34 to 0.48)

Reduction value TD%

XTI- - XTR
XTE

29

52

b) 4 ^/ -chlorophenoxyisobutynite of N-cyclohexyl-aminocarbonylpropyl alcohol

product

Control (gum arabic solution). . . .

Product according to the invention

100 mg kg

400 mg / kg.

Whom of the Cholcstcrm- Minierer Unlerschiei halls μ, Ί serum XTK XTK 0.79 (0.5 «to 1.03) 0.66 0.13 + (0.53 to 0.92) 0.46 0.33 + I- (0.40 to 0.55)

Verriniicrungswcrl IT) '

16

42

c) 4'-chlorophenoxyisobuyral of 3-benzyloxycarbonylpropyl alcohol

- ■■■ - · ■ τ

Prcxluct
Control (gum arabic solution) ....

Product according to the invention

100 mg / kg

400 mg leg.

Value of the cholesterol g Ι serum

0.65
(0.56 to 0.71)

0.56
(0.4X to 0.61)

0.50 (0.41 to 0.56)

Medium difference

0.09 + 0.15-t- l -

Vcrringerui ^ swerl TI) '

14th

23

d) 4'-bromophenoxyisobutyral of 3-ethoxy carbonyl propyl alcohol

product

Control (cjumm arabic solution) ....

Product according to the invention

100 mg kg

400 mg kg.

Who! of the choleslering jruilts i! 1 serum

0.59 10.49 to 0.73)

0.56 (0.48 to 0.70)

0.45 (0.34 to 0.551

Medium difference! Reduction ratio Ί I) '

0.03 0.14+ +

24

e) 4'-Chlorophenoxyisobutyrate of 3- (Dimethylaminociirbonyl) propyl alcohol

This product was tested beforehand (one week of treatment) and continued after two weeks of treatment.

Treatment for one week

Product value of the cholesterol level g / l serum

Mean difference XTE-XTR

Reduction value TD%

XTE-XTR XTE

Control (gum arabic solution) ....

Product according to the invention

100 mg / kg

400 rig / kg.

0.74 (0.61 to 0.87)

0.65 (0.56 to 0.77)

0.57 (0.50 to 0.70)

0.09 + 0.17+ +

12 23

Treatment for two weeks

(fo

product

Control (gum arabic solution). . . .

Product after the discovery

lOOmgAg

4 (X) mg / kg.

Value of the Cholcslering Sound g'l serum

0.65 (0.46 to 0.75)

0.52 (0.43 to 0.60)

0.46 (0.29 to 0.63)

Minierer difference
XTE XTR

0.13+ +
0.19+ +

Reduction.vcrt TD% XTJL_XTR

XTI-:

20th
29

The above results show that the found products are a significant one Show effectiveness at 100 or 400 mg, kg animal weight by the oral route.

Therapeutic use

The products are, for example, in the form of sugar-coated tablets or capsules, each Contains 200 mg of active ingredient, with a daily dose of 2 to 10 tablets or capsules to sick mil administered at high levels of cholesterol.

The characteristic representative of the previously known Compounds with cholestcrin-lowering effect is the one under the Ircien international Abbreviation "chlofibrate" known ethyl ester of p-chlorophenoxy-isobutyric acid. This product is universally known for combating hypercholestcrinemic and is used all over the world sold under various trade names. It is a product of excellent Effect and very great importance.

In spite of the successful and extensive clinical use of c'lofibrate, however, demonstrated that this product potentializes the effects of anticoagulants. which is common in treatment of coronary athcrosklcrosc occur. The object of the present invention was therefore Manufacture of compounds that are more effective and safer than this product Offer.

The esters according to the invention of p-chlorophenoxyisobutyric acid fulfill this task. They are choleretic about theirs Beneficial effect on liver cells and anticoagulants potentialize considerably less than the chlofibrate.

This superior action of the compounds according to the invention - to be demonstrated in more detail below compared to the best known comparable compound was known to the person skilled in the art through the prior art not suggested. The compounds according to the invention differ from the majority of the known Derivatives of p-halophenoxyisobutric acid by the fact that they are capable of these To regenerate acid in the organism.

To demonstrate the advantageous action of the compounds according to the invention, comparative tests were carried out using a compound according to the invention of the general formula given at the beginning, in which X is a chlorine atom and R is the group - N (CH ₃ J _2. This compound is referred to below as VII 8 .

The compound according to the invention shows when taken orally and intrapcritonal application in mice and rats a toxicity which is exactly of the order of magnitude that of the c'hlofibrals. The hypocholemic and hypolipemic effects are equal Doses in rats (per os) at least as intense as those of the reference substance.

However, the compound according to the invention shows three decisive advantages over clofibrate:

I. It has a chemical effect in rats and oral administration, as the following test results make clear.

product

VII 8
Clofibrate

dose

mg kg

p. O.

400

SOO
400
800

(holerese change in "■.

Cholcrese

2 hours after

administration

of the product

+ 25
+ 27
+ 2
+ 16

Cholcrese. ' and

4 hours after

Administration:

of the product

+ 10
+ 10.5

0
+ 6

2. The anticoagulant effect of the anti vitamins K is less potentialized, an effect which clofibrate does not have in rats.

Products dose mgAg 50 Control substance p. O. 3- (ff-phenyl- / i-acetyl- _ ethyl) -4-hydroxy- 55 coumarin-Na 3 - («- phenyl- / i-acetyl- 0.1 ethyl) -4-hydroxy- coumarin-Na VII 8 0.1 6o 3 - («- Phenyl - ^ - acctyl- 400 ethylH-hydroxy- coumarin-Na Clofibrate 0.1 65 400

Time after
Quick
in seconds

14th

16

25th

35

Time after H ο w e I I

in
Seconds

152

2i8

3. The gastric tolerance is that of the clofibrate think about it - like this on R? »ten according to A. R ο b e r t

11th

and .1. E. N e ζ a m i s. Proc. Soc. Exj ... Biol. Med .. (1953), restgestclll, which were fixed for 4 days and liquid food was deprived.

Products

Dose in mg kg

100 400

Ulcerogenic activity in pats

1.3

1."

Products

C'lol'ibrat

Dose in mg leg

100
400

Ulcerogenic activity in rats

1.0

2.7

The pharmacological comparison experiments thus show that the connection according to the invention compared to c'lofibrate has the advantage of activating the C'holcresc and better tolerability as well as causing fewer side effects.

Claims (1)

Patent claims: 1. p-chloro- or p-bromo-phenoxyisobutyric acid ester the general formula CH ₃
) -C-CO-O-CH, CH, CH ₁ -COR CH ₃ in which X is a chlorine or bromine atom and R is an alkoxy group with up to 3 carbon atoms, a benzyloxy or a