DE2263110C3 - - Google Patents

Description

is a halogen atom or the trifluoromethyl group.

and R ^{2 are} identical or different and are hydrogen atoms or aliphatic, straight-chain or branched hydrocarbon radicals having 1 to 5 carbon atoms, and

R3 is a hydrogen atom, an alkanoyl radical or represents a halophenoxyalkanoyl radical, the alkanoyl radicals in each case Contain 1 to 5 carbon atoms.

2. Process for the preparation of the triazines according to claim 1, characterized in that one is in on a known way a phenoxyalkanecarboxylic acid of the general formula (II)

1'

O — C — COOH

in the X, Ri and R2 the aforementioned meaning have, or a reactive derivative of the phenoxyalkanecarboxylic acid of the formula (II), with phenylethylbiguanide of the formula

^ "CH ₂ CH ₂ NH-C-NH-C-NH ₂ NH NH

converts, and optionally the amino group in the 2-position of the triazine with a corresponding one Alkanecarboxylic acid or halophenoxyalkanecarboxylic acid or a reactive derivative thereof Acylated acids in a manner known per se.

3. Medicines, characterized by a content of one or more compounds according to Claim I.

CH ₂ CH ₂ N

NHR ₃

in the

a

Halogen atom group is

or the trifluoromethyl

and Ra are identical or different and hydrogen atoms or aliphatic, straight-chain or branched hydrocarbon radicals with 1 to 5 carbon atoms mean, and

Rj is a water atom, an alkanoyl radical or represents a halophenoxyalkanoyl radical The alkanoyl radical or the alkanoyl part each consists of 1 to 5 carbon atoms.

Preferred halogen atoms are chlorine and fluorine. Chlorine is particularly preferred, especially in the p-position.

Examples of suitable hydrocarbon radicals are alkyl radicals, such as methyl, ethyl, propyl, Isopropyl, η-butyl, sele-butyl, tert-butyl or n-pentyl groups, and also branched pentyl groups. Alkyl radicals with 1 to 3 carbon atoms are preferred. the

Methyl group is particularly preferred

Specific examples of alkanoyl radicals are the formyl, acetyl, propionyl, butyryl or pentanoyl groups. Alkanoyl radicals with 1 to 3 carbon atoms are preferred The acetyl group is particularly preferred.

Preferred halophenoxyalkanoyl radicals have 1 to 3 carbon atoms in the alkanoyl radical. Specific examples suitable alkanoyl radicals are mentioned above. The 2- (p-chlorophenoxy) propionyl group is particularly preferred.

4-, Those triazines of the general formula (I), the have a free amino group, form salts with inorganic and organic acids. examples for suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phos- phosphoric acid, formic acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, tartaric acid, Lactic acid, malic acid or citric acid.

The invention also relates to a process for the preparation of the triazines of the general formula (I), which is characterized in that a phenoxyalkanecarboxylic acid is known in the art general formula (II)

■ O — C — COOH

in which X, Ri and R2 have the aforementioned meaning, or a reactive derivative of the phenoxyalkanecarboxylic acid of the formula (It), with the phenylethylbiguanide

formula

- C - NH - C - NH ₂

NH

NH

reacts, and optionally the amino group in the 2-position of the triazine with a corresponding alkanecarboxylic acid or halophenoxyalkanecarboxylic acid or a reactive derivative of these acids acylated in a manner known per se

The reaction of the phenoxyalkanecarboxylic acid is preferably carried out in a suitable solvent, such as Chloroform or an alcohol, e.g. B. ethanol, and in the presence of a catalyst such as phosphorus oxychloride, phosphorus trichloride or polyphosphoric acid, performed.

When using reactive derivatives of phenoxyalkanecarboxylic acid, of which alkyl esters, acid anhydride and acid halides can be preferred can be used in the absence of a catalyst.

Surprisingly, the preparation of the triazines according to the invention is particularly easy if the phenylethyl biguanide base with an alkyl ester the phenoxyalkanecarboxylic acid in an inert solvent such as chloroform in the absence of one Catalyst converts.

If Ri and Ra are hydrogen atoms, the reaction is complete after a few hours at room temperature. If Ri and R _{2 are} alkyl radicals, heating under reflux of the solvent is necessary. This type of reaction offers the great advantage that the complex process for the preparation of the acid halide or acid anhydride is omitted, whereby a very simplified and gentle preparation of the triazoles according to the invention is possible

The triazines of the general formula (I) have a marked lowering of cholesterol and lipids Effect that exceeds the well-known antilipaemic clofibrate (p-chlorophenoxyisobutyric acid ethyl ester) many times over. They are characterized by good tolerability and low toxicity, as follows still shown on the basis of test investigations

Surprisingly, it was also found that the triazines of the extremely low dosage Invention can potentiate the therapeutic effect of clofibrate.

The medicaments of the invention contain one or more triazines of the general formula (I) as Active ingredient. It is preferably used orally, e.g. B. in the form of capsules or tablets, the optionally customary pharmaceutical carriers and Tools included.

The preparation of the new compounds is described in the following examples.

example 1

9.35 g (45, SmMoI) of crystalline Phenyläthylbiguanid-Base, from the corresponding hydrochloride by Alkalizing was obtained, is dissolved in 200 ml of chloroform with gentle heating and filtered. The filtrate is mixed with 21.4 g (0.1 mol) of ethyl p-chlorophenoxyacetate and then for 6 hours stirred at room temperature. After only about 2 hours, the reaction product starts from the previously clear one Solution fail. The crystals are filtered off with suction washed a little chloroform and dried. That so obtained crude product (14.4 g) is suspended in 200 ml of water with stirring and, after standing, over Sucked off at night 13.3 g (82.1% of theory) 2-Amino-4- (2-phenyIäthylamino) -6- (p-chlorophenoxymethyl) -l, 3,5-triazine obtained 190-92 ⁰ C as a colorless crystallizate of melting point. A sample crystallized from ethanol has a melting point of 193-95 ° C. Further recrystallization can make the

ίο Melting point can be brought to 194-195 "C.

Elemental analysis: Ci ₈ Hi _{8 ClN 5} O (355.8)

Calculated: C 60.76, H 5.10, N 19.69, Cl 9.97, Found: C 60.74, H 5.14, N 19.93, Cl 9.69.

IR (KBr):

3510 / cm 0-NH ₂ ) 3260, 3120 / cm (-NH) 1660, 1640 / cm (ONH ₂ ) 1572 (γ ring) 1242, 1010 / cm (COC) 828, 809, 750, 705 / cm

Example 2

24.1 g (0.1 mol) of phenylethyl biguanide hydrochloride are dissolved in water and made alkaline with sodium hydroxide solution and extracted with 200 ml of chloroform in portions. The dried with sodium sulfate and filtered Chloroform solution is mixed with 30.3 g (0.1 mol} 2- (p-chlorophenoxyj-propionic acid inhydride and 1 hour The heated under reflux with dilute sodium hydroxide solution and water-washed chloroform phase is evaporated on a rotary evaporator and the distillation residue is crystallized from aqueous isopropanol. 19.0 g (53% of theory) of 2-amino-4- (2-phenyI-ethylamino) -6- [l- (p -chlorphenoxy) -ethyl] -l, 3 _I 5-triazine obtained from melting point 152-54 ° C. Recrystallization from a little ethanol gives colorless needles from Melting point 154 ° C. By further recrystallization the melting point can be brought to 156-157 ° C.

Elemental analysis: Ci ₉ H _{20 ClN 5} O (369.8b)

Calculated: C 61.70, H 5.45, N 18.34, Cl 9.58; Found: C 61.65, H 5.50, N 18.74, CI

IR (KBr):

3510 / cm (γ NH ₂ ); 3280, 3125 / cm (-NH), 1655 {6 NH ₂ ) 1605, 1575 / cm (y ring); 1238, 1015 / cm (COC) 832, 825 / cm.

NMR (CDCIj / 60 MHz): δ = 1.68 (d, 3H); <5- 2.96 (m, 2H); δ = 3.76 (m; 2H); 6 = 4.93 (d, IH) total proton number: 20 H.

Example 3

203 g (0.1 mol) of phenylethyl biguanide base are used with the addition of 50.0 g (0.2 mol) of 2- (p-chlorophenoxy) isobutyric acid ethyl ester dissolved in 100 ml of ethanol and Heated under reflux for 5 hours. The received Solution is evaporated and the excess gently distilled off on ethyl p-chlorophenoxyisobutyrate in an oil pump vacuum. The residue is crystallized from aqueous ethanol, with 11.5g (30% of theory) 2-amino-4- (2-phenylethyl-

_b are obtained 5-amino) -6- [2- (p-chlorophenoxy) -isopropyl] -13.5-triazine of melting point 141 -43 ⁰ C. The melting point can be brought to 145-146 ° C by further recrystallization.

22 63 UO

Elemental analysis; C ₂₀ Hj ₂ ClN ₅ O (383.9)

Calculated; C 62.58, H 5.77, N 18.24, Cl 9.23;
found; C 62.61, H 5.83, N 18.23, C] 9.29

IR (KBr):

3520 / cm (y NH ₂ ) 3280, 3145 / cm (NH) 1650 (ö NH ₂ )
1615 / cm; 1250, 1015 / cm (COC); 832, 702 / cm.

NMR (CDCl3 / 60 MHz):

ό = 1.69 (s, 6H); δ = 2.95 (m, 2H);
δ = 3.76 (m, 2H)
Total number of protons: 22 H.

Example 4

20.5 g (0.1 mol) of phenylethyl biguanide base and 40.8 g (0.22 mol) of p-chlorophenoxyacetic acid are in Suspended 100 ml of toluene and, after adding 9.6 g of phosphorus oxychloride, heated under reflux for 4 hours The reaction solution is stirred with dilute sodium hydroxide solution and the crystals obtained are filtered off with suction

The crystals are crystallized from aqueous ethanol, whereby 16.7 g (47% of theory) 2-amino-4- (2-phenyl-

ethylamino) -6- (p-chlorophenoxymethyl) -1,3,5-triazine
with a melting point of 189-91 ° C. The melting point can be brought to 194-195 ° C. by further recrystallization.

Example 5

18.5 g (0.05 mol) of 2-amino-4- (2-phenylethylamino) -6- [1- (p-chlorophenoxy) ethyl] -1,3,5-triazine, melting point 152-154 ° C are refluxed in 27.7 g (0.25 mol) of acetic anhydride for 6 hours and the excess acetic anhydride is distilled off in vacuo. The residue is crystallized from isopropanol, 12.4 g (60.5% of theory) of 2-acetylamino -4- (2-phenylethylamino-6- [1- (p-chlorophenoxy) ethyl] -13.5-triazine
with a melting point of 138-40 ° C.

The constitution results from the lack of those typical for the triazines with a free, primary amino group Band at 3500 / cm in the IR / spectrum, as well as by the appearance of a carbonyl band at 1690 / cm.

IR (KBr):

3220 / cm (-NH); 1690 / cm (C = O); 1580, 1545,
1460, 1190, 830 / cm.

Example 6

18.5 g (0.05 mol) of 2-amino-4- (2-phenylethylamino) -6- [1- (p-chlorophenoxy) ethyl] -13,5-triazine and 20.8 g (0.06 mol) of 2- (p-chlorophenoxy) propionic anhydride are refluxed in 200 ml of xylene for 6 hours heated. The xylene solution washed with dilute sodium hydroxide solution and water is used on a rotary evaporator evaporated, dissolved hot in isopropanol and mixed with a little water until slightly cloudy.

7.7 g (28% of theory) 2- [2- (p-chlorophenoxy) propionylamino] -4- (2-phenylethylamino) -6- [1- (p-chlorophenoxy) ethyl] - 1,3,5-triazine obtained from melting point 170-74 ° C. By further recrystallization the melting point can be brought to 174-176 ° C will.

The constitution results from the lack of being used for that. Triazine typical gang 3500 / cm, as well as the appearance of a carbonyl band at 1690 / cm.

IR (KUr);

3270, 3160 / cm (-NH); 1690 / cm (C = O); 1600 / cm 1240, 1010 / cm (C-O-C); 832, 828, 700 / cm.

Example 7

9 ^ 5 g (45.5 mmol) of phenylethyl biguanide base and 12.8 g (0.06 mol) of ethyl o-chlorophenoxyacetate are, as described in Example 1, reacted. The filtered chloroform solution is evaporated and off Recrystallized ethanol with the addition of water

7.6 g (47% of theory) of 2-amino-4- (2-phenylethylamino) -6- (o-chlorophenoxymethyl) -1,3,5-triazine are obtained obtained from melting point 103-105 ° C.

IR (KBr):

3498 / cm (y NH ₂ ); 3260 / cm (-NH); 1660, 1645 / cm (ό NI I ₂ ) 1242, 1008 / cm (COC); 808, 745, 702 / cm.

Example 8

9 35 g (45.5 mmol) of phenylethyl biguanide base and 27.5 g (0.1 mol) of 2- (m-trifluoromethylphenoxy) -2-methylpropionic acid ethyl ester are refluxed in 150 ml of chloroform for 5 hours. After evaporation the excess ethyl ester is distilled off from the solution in an oil pump vacuum. The still residue is redissolved in chloroform and successively with dilute sodium hydroxide solution, dilute hydrochloric acid and Water washed. After evaporation of the solution

j5 remain 11.6g (62%) 2-amino-4- (2-phenylethyl-

amino) -6- [2- (m-trifluoromethylphenoxy) isopropyI] -13,5-triazine as a yellowish oil that could not be made to crystallize. According to DC, that is Product still contaminated with about 2% Phenyläthylbiguaaid.

IR (film):

3510 / cro (NH ₂ ); 3280, 3135 / cm (NH); 1650 / cm (NH ₂ )

Example 9

117.8 g (1.0 mol) of potassium t-butoxide are in 1400 ml of methanol are dissolved and 241.6 g (1.0 mol) of phenylethylbiguanide HCl are added in portions. Afterward within about 30 minutes 244.0 g (1.0 mol) of 2- (p-chlorophenoxy) -2-methylprop'onic acid ethyl ester added dropwise.

After complete addition, the mixture is stirred for 8 hours at 40 ⁰ C of iiner lnnentemperatui After standing overnight, with stirring, 700 ml water was added and the crystals are filtered off with suction. The still moist crystals are cut into approx.

Suspended 200 ml of water with stirring and suctioned off again.

There are 268.5 g (70% of theory) 2-AnUnO - * - (2-phenyläthyIamino) -6- [2- (p-chlorophenoxy) isopropyl] -13,5-triazine obtained as colorless crystals with a melting point of 145-146 ° C.

In the following table I a compilation given the prepared triazines according to the invention.

Table I. CH ₂ NH-
t CH, 22 63 110
7th R, 8th C ₆ H _4n -Cl yield animal M.p. "C CH, H 74.2 A rat
B rat
C rat
C mouse
_b5 F mouse
P mouse
Q mouse
*) According to Spearman-Kärber. 194-95 R ₁ N
MN
T
-CO / \ H 69.7 I56 -57 Ver X
binding H CH, i χ
R ₂ ^X H -C ₆ H ₄₀ -Cl 70.0 \ 4 $ 46 Λ p-CI CH, CH, R, H 47.0 103-05 B p-CI CH. H H , H _4n -Cl 62.0 oily I. C p-CI H CH, H H 71.6 204-05 D o-CI CH, r / H. H H ₄₀ -F 68.7 200-01 E m-Ci H CH, H H H _4n -Cl 54.6 164-65 <, F p-j H CH, H 48.0 112 G p-Br H H H 74.8 130-31 H p-CI H H H 52.7 103-04 I. J o CI H (CHj) ₂ CH- H 64.3 78-79 K p-F CH, (CHj) ₂ CHCH ₂ - -COCH, 60.5 138-40 L p-CI M m-CF, H CH, - COCH —O - 52.6 174-76 N p-CI C ₂ H ₅ CH, O p-CI CH, -COCH ₂ OQ 64.0 168-70 H - CO-CH-O 53.7 129-30 P p-CI H CH, Q P-ci —Coc — o — c, 36.8 124-25 CH, (CH,) ₂ R p-CI CH, -COCH ₂ OC ₆ 56.0 145-46 -COCH ₂ OC ₆ 11.8 133-35 S p-CI CH, 55 The observation period was 3
Test results were as follows: Weeks. Tuesday T p-CI Test substance LDjo
(mg / kg) H > 4000
> 4000
> 4000
> 12 500)
> 12 500)
> 12500 ·)
>! 2 500 ") H acute toxicity The acute toxicity of the compound according to the invention
tests were carried out on rats (Sprague-Dawley), as well
NMRI mice studied
Compounds A, B, and C were on five each
female and male rats, weighing
from 140-185 g, perorally, using a pharynx in one
aqueous bolus Jba mash administered
Compounds C, F, P and Q were in water
emulsified with the help of Tween 80 and in one
Volume before 1 ml / animal mice of about 20 g weight
administered orally by means of a gastric tube

10

If doses higher than 12,500 mg / kg were administered, apathy persisted for several hours, Accelerated breathing and reluctance to eat, but no mortalities were found, also after Withdrawal no pathological-anatomical changes.

In contrast, the LDw value of clofibrate is (p - ..: ethyl chlorophenoxyisobutyrate) 1150 mg / kg.

Anti-lipemic efficacy

The anti-lipemic effectiveness of the invention Substances B, C, O, P according to Table I and of clofibrate as a reference substance were in one three-stage model experiment on normolipemic SPF Wistar rats (10 animals / group each), using an oral Administration examined over a test period of 14 days.

at oiüriuf; n üeiCii ucf bitten / AppiiKäüuil uci

Substances or the vehicle, blood samples were used to determine the serum cholesterol and triglyceride levels taken.

In the first series of experiments, the effectiveness of the compounds was determined on rats that were exposed to the received a normal laboratory diet throughout the test period. The results of this series are shown in Table II summarized.

In a second series of experiments, which was carried out parallel to the first series, the animals received a high cholesterol diet (fat diet I; according to Berger et _l., Proc. Soc. Ex. Biol. [1969], 132, 293).

In a third series of tests, the effectiveness determined on young male rats (weight 80-90 g) that were enriched with cholesterol and butter Diet (fat diet 2;) were fed over the entire test period.

The results of these two series of tests are summarized in Table III.

The statistical significance ρ of the results is also indicated.

Table II

Antilipemic efficacy in rats (p. O.) Under normal diet:

test
group Dosie
tion
mg% Endwerl
Cholest.
mg% Changes
tion
% F.ndwerl
Triglyz. Ver
changes
tion
% control - 76.9 - 123.8 - B. 100
250 74.6
75.5 -3.0
-1.8 O 100
250 73.8 -4.0 89.6 ")
81.0 ···) -27.6
-34.6 P. 100
250 68.8 ^# )
66.3 *) -11.5
-13.8 Clofibrate 250
10001) 56.1 ···)
68.0 *) -27.0
-11.6 66.5 ")
63.3 * ··) -46.3
-48.9

ρ <0.05.
ρ <0.01.
ρ <0.001.

3 out of 10 animals died during the test period.

Table III • ρ <0.05. Final value Ver Final value Fat Diet I as well as cholesterol and Ver enriched butter Ver ♦ # ρ <0.01. Cholest. changes Triglyz. changes changes ρ <0.001. tion Fcttdu '2 tion tion 1 mg% % Ver Endwerl % Final value % Anti-lipemic efficacy among hypercholesterolemic 358.6 - 86.4 changes Cholest. - Triglyz. - the fat diet 2 343.2 - 4.3 84.7 tion Test group fat diet 1 395.7 *) + 10.3 70.0 *) % mg% dosage 123.1 -9.0 135.7 - 6.5 351.6 - 2.0 91.6 - 2.0 362.4 + 1.1 124.0 -19.0 mg / kg 381.9 + 63 96.7 112.0 126.9 Control - 458.2 * · *) + 27.8 12U) + 6.0 B 100 347.9 - 3.0 75.6 + 43.5 + 8.3 -20.6 250 245.4 * ") -31.6 1203 + 113 C 100 + 40.3 O 100 -12.5 133.3 107.7 *) 250 + 39.2 P 100 3 out of 10 animals died. 250 Clofibrate 250 1000 ')

If one compares the test results for compounds B, C, O and P with those of the clofibrate, it gives a differentiated spectrum of activity. The triazines B and C unsubstituted on the N atom are clofibrate superior in effectiveness under fat load. The triazines O and P substituted on the N atom show as the clofibrate only has a good effectiveness under normal diet, namely compound O especially against increased Triglyceride levels and compound P against high cholesterol levels. In connection with the very low Toxicity of the compounds according to the invention, however, is clearly superior to clofibrate

Il

therapeutic index. The compounds according to the invention can thus be used as active therapeutic agents both with and without additional dietary measures for the treatment of diseases with increased serum cholesterol and triglyceride values, such as i. B.> Atherosclerosis or special metabolic disorders can be used.

Claims (1)

Patent claims: 2-Amino-4-pbenyIäthyIamino-6-phenoxymeii of the general formula (I) CH ₁ CH ₁ N in the The invention relates to 2-amino-4-phenylethylaminoe-phenoxymethyl-IrS-S-triazines of the general formula (I)