DE2263110B2 - 2-Amino-4-phenylethylamino-6-phenoxymethyl-1 ^ -triazines and process for their preparation - Google Patents

Description

) —C — COOH

(H)

^ CH ₂ CH ₂ NH-C-NH-C-NH ₂
NH NH

The invention relates to 2-amino-4-phenylethylaniino-6-phenoxymethyl-lßi-triazine of the general formula (I)

ίο

15th

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

Ri is a hydrogen atom, an alkanoyl radical or a halophenoxyalkanoyl radical represents, the alkanoyl radicals each containing 1 to S 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)

25th

30th

35

40

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

in the

a halogen atom or the trifluonethyl group is,

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 of these acids acylated in a manner known per se.

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

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

R3 represents a hydrogen atom, an alkanoyl radical or 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, sec-butyl, tert-butyl or n-pentyl group, furthermore 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 have been mentioned above. The 2- (p-chlorophenoxy) propionyl group is particularly preferred.

Those triazines of the general formula (I) which have a free amino group form salts with them inorganic and organic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, 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 further 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 the X, Ri and R? have the aforementioned meaning or a reactive »derivative of phenoxyalkanecarboxylic acid of the formula (II), with phenylethyl biguanide

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 Tristzins with a corresponding alkanecarboxylic acid or halophenoxyalkanecarboxylic acid or a reactive derivative of these acids per se known way acyüert

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 Presence of a catalyst such as phosphorus oxychloride id, phosphorus trichloride or polyphosphoric acid, performed.

When using reactive derivatives of phenoxyalkanecarboxylic acid, of which are alkyl esters, acid anhydride and $ «urehak> genide can be preferred can be operated in the absence of a catalyst.

Surprisingly, the preparation of the triazines according to the invention is particularly easy if the Pheny la thy! biguanid 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 R _{2 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 conversion offers the great advantage that the laborious process for the preparation of the acid halide or acid anhydride is omitted, so that a very simplified, at * -protective preparation of the triazines according to the invention is possible

The triazines of the general formula (I) have a pronounced cholesterol- and lipid-lowering effect Effect that the well-known antilipaemicum clofibrate (p-chlorophenoxyisobutyric acid ethyl ester) many times over They are characterized by good tolerance 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, optionally Contain conventional pharmaceutical carriers and auxiliaries.

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

example 1

9.35 g (45.5 mmol) of crystalline phenylethyl biguanide base, which was obtained from the corresponding Hydrochloric) by alkalizing, is in 200 ml Chloroform dissolved with slight warming and filtered. The filtrate is treated with 21.4 g (0.1 mol) of ethyl p-chlorophenoxyacetate added and stirred for 6 hours at room temperature. After about 2 hours, the reaction product begins from the previously clear Solution fail. The crystals are filtered off with suction

Washed a little chloroform and dried. The crude product obtained in this way (14.4 g) is suspended in 200 ml of water with stirring and, after standing overnight, is filtered off with suction. 133 g (82.1% of theory) of 2-amino-4-12-phenylethylammo are obtained ) -6- (p-chIorphenoxymethyl) - 3,5-triazine as colorless crystals of melting point 190-92 ⁰ C. A sample crystallized from ethanol shows a melting point of 193-95 ° C. The melting point can be brought to 194-195 ° C. by further recrystallization.

Elemental analysis: Ci ₈ Hi _{8 ClN 5} O (3553)

Calculated: C 60.76, H 5.10, N 19.69, Cl 9.97,
Found: C 60.74, H 5.14, N 1933, α 9.69.

Ik (KBr):

3510 / cm 6> NH ₂ ) 3260.3120 / cm (-NH) 1660,
1640 / cm (ONH ₂ ) 1572 (y 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 in portions with 200 ml of chloroform The chloroform solution, dried with sodium sulfate and filtered, contains 303 g (0.1 mol) of 2- (p-chlorophenoxy) propionic anhydride added and heated under reflux for 1 hour with dilute sodium hydroxide solution

jo and water-washed chloroform phase is evaporated on a rotary evaporator and the distillation residue Crystallized from aqueous isopropanol. 19.0 g (53% of theory) of 2-amino-4- (2-phenylethylamino) -6- [l - (p-Chlorophenoxy) ethyl] -13,5-triazine

j5 obtained with a melting point of 152-54 ° C. The recrystallization from a little ethanol gives colorless needles with a melting point of 154 ° C. Further recrystallization the melting point can be brought to 156-157 ° C.

Elemental analysis: C ₁₉ Hi ₀ CIN ₅ O (369.86)

Calculated: C 61.70, H 5.45, N 1834, Cl 9.58;
Found: C 61.65, H 5.50, N 18.74, Cl 1031.

IR (KBr):

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

NMR (CDClj / 60 MHz):
δ - 1.68 (d, 3H); δ - 2.96 (m, 2H);
(J - 3.76 (m; 2H); (J = 4.93 (d, IH)
Total number of protons: 20 H.

Example 3

20.5 g (0.1 mol) of phenylethyl biguanide base are used with the addition of 50.0 g (0.2 mol) of ethyl 2- (p-chlorophenoxy) isobutyrate dissolved in 100 ml of ethanol and refluxed for 5 hours. The solution obtained is evaporated and the excess of ethyl p-chlorophenoxyisobutyrate im Oil pump vacuum distilled off gently. The residue is crystallized from aqueous ethanol with 11.5g (30% of theory) 2-amino-4- (2-phenylethyl-

amino) -6- [2- (p-chlorophenoxy) -isopropyl] -13,5-triazine of melting point 141 -43 ^e C are obtained. By further recrystallization the melting point can be raised to 145- 146 C ^e.

Elemental analysis: C ₂₀ H ₂ JaNsO (383.9)

Calculated: C6S! £ 8, H 5.77, N 18.24, Cl 9.23;
Found: C 62.61, H 5.83, N 18.23, Cl 9.29

IR (KBr):

3520 / cm (y NH ₂ ) 3280.3145 / cm (NH) 1650 (O NH ₂ ) 1615 / cm; 1250, 1015 / cm (COQ; 832, 702 / cm.

NMR (CDCl3 / 6O MHa):

δ - 1.69 (s, 6H); δ - 2 £ 5 (m, 2H);
δ - 3.7t> (in, 2H)
Total number of protons: 22 R.

Example 4

20.5 g (0.1 mol) of phenylethyl biguanide base and 40.8 g (0.22 mol) of p-CWorpbenoxyessigsiure 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-Amho-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 crystallization

Example 5

18.5 g (0.05 mol) of 2-amino-4- (2-phenylethylamino) -6- [1- (p-chlorophenoxy) ethyl] -l, 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- [l- {p-chlorophenoxy) ethyl] -l, 3,5-triazine are obtained of melting point 138-40 ⁰ C.

The constitution arises from the absence of the for the triazines with free, primary amino group typical band at 3500 / cm in the IR / Sepktnim, as well as by the Appearance of a carbonyl band at 1690 / cm.

IR (KBr):

3229 / cm (-NH); 1690 / cm (CO); 1580, 1545,
1460, 1190, 830 / cm.

Example 6

18.5 g (0.05 mol) 2- \ mino-4- (2-phenylethylamino) -6- [1- (p-chlorophenoxy) ethyl] -1.3.5-triazine and 20.8 g (0.06 mol) of 2- (p-chlorophenoxy) propionic anhydride are refluxed in 200 ml of xylene for 6 hours The xylene solution, washed with dilute sodium hydroxide solution and water, is heated 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 ^ H ^ -phenyläthylaminoJ-e-fl-ip-chlorophenoxy) -8thyl] -1, 3-5- triazine obtained 170-74 ⁰ C of melting point. The melting point can be brought to 174-176 ° C. by further recrystallization.

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

IR (K3r):

3270, 3160 / cm (-NH); 1690 / cm (CO); 1600 / cm
1240.1010 / cm (COQ; 832.828, 700 / cm.

Example 7

935 g (45.5 mmol) phenylthyl biguanide base and 123 g (0.06 mol) of o-chlorophenoxyacetethyl ester are, as described in Example 1, implemented filtered chloroform solution is evaporated and off

Recrystallized ethanol with the addition of water

There are 7.6 g (47% ATh.) 2-Amino-4- (2-phenyI-ethylamino) -6- {o-chlorophenoxyinethyl) -1, 3 ^ - triazine
103-105 ⁰ C obtained from the melting point.

IR (KBr):

3498 / cm (γ NH ₂ ); 3260 / cm (-NH); 1660.1645 / cm
(<J NH ₂ ) 1242, 1008 / cm (COQ;
808, 745, 702 / cm.

Example 8

935 g (45.5 mmol) of phenylethyl biguanide base and 27p g (0.1 mol) of ethyl 2- (m-trifluoromethylphenoxy) -2-methylpropionate are refluxed in 150 ml of chloroform for 5 hours.

The excess ethyl ester is distilled off in the solution in an oil pump vacuum. The distillation residue is redissolved in chloroform and successively with dil sodium hydroxide solution, dil hydrochloric acid and Water washed. After evaporation of the solution, 11.6g (62%) of 2-amino-4- (2-phenyläthyI-

amino) -6- [2- (m-trifluoro-methylphenoxy) -isopropyl] -13 ^ -triazine as a yellowish oil that could not be made to crystallize. According to DC, that is Product still contaminated with about 2% phenylethyl biguanide

IR (film):

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

Example 9

117.8 g (1.0 mol) of chewing t-butoxide are dissolved in 1400 ml of methanol and 241.6 g (I ₁ OMoI) of phenylethyl biguanide HCl are added in portions over the course of about 30 minutes , 0 mol) 2- (p-chlorophenoxy) -2-meth; ethyl propionate was added dropwise

.5 After complete addition, the mixture is stirred for 8 hours at an internal temperature of 40 ⁰ C. After your stand overnight with stirring 700 ml of water was added and filtered off with suction, the KristalHsat. The still moist crystals are cut into approx.

Suspended 200 ml of water with stirring and suctioned off again

2684 g (70% of theory) of 2-amino-4- (2-phenylethylamino) -6- {2- (p-chlorophenoxy) -isopp> p> i} -13f5-triazine are obtained obtained as colorless crystals with a melting point of 145-146 ° C.

A summary is given in Table I below given the prepared triazines according to the invention.

22 63 ΠΟ

Table 1

CH ₂ CH ₂ NH -f * ^ pNHR ₃
NN
T

Ver
binding χ R ₁ R ₁ R ₁ yield
V. Fp-C A. P-Cl H H H 74.2 194-95 B. P-Cl CH, H H 69.7 156-57 C. p-CI CHj CH ₃ H 70.0 145 46 D. o-Cl H ti H 47.0 103-05 ε; m-CF, CH, CH, H 62.0 oily F. p-J H H H 71.6 204 05 O p-Br H H H 68.7 200-01 H p-CI H (CH ₃ I ₂ CH- H 54.6 164-65 J o-CI H (CH ₁ I ₂ CHCH ₂ - H 48.0 112 K p-F H CH, H 74.8 130 -31 L. p-CI CH, C ₂ H ₅ H 52.7 103-04 M. m-CF, H CH ₃ H 64.3 78-79 N p-CI CH, H -COCH ₃ 60.5 138-40 O P-Cl CH, H -COCH-OC ₆ H ₄₁₁ -CI 52.6 1 74-76 CH ₃ P. P-Cl CH, CH, -COCH ₂ OC ₆ H ₄ ^ -CI 64.0 168-70 Q p-C-1 CH, CH, -CO-CH-OC ₆ H ₁₁₁ -Cl 53.7 I 29-30 CH ₃ R. P-Cl CH, CH, -COC-OC ₆ H ₄ ^ -Cl 36.8 1 24-25 (CH ₃ ) ₂ S. P-Cl CH, H -COCH ₂ OC ₆ H ₄₁₁ -F 56.0 145-4. T p-CI H H -COCH ₁ OC ₆ H ₄₀ -Cl 11.8 133-35

acute toxicity

The acute toxicity of the compounds according to the invention was tested on rats (Sprague-Dawley), as well NMRI mice studied

Compounds A, B and C were tested on five female and five male rats, weighing from 140-185 g, perorally, using a pharynx in one aqueous bolus alba porridge administered

Compounds C, F, P and Q were in water with help before. Tween 80 and emuiged in one Volume of 1 ml / animal administered orally to mice weighing about 20 g by means of a pharyngeal tube.

The observation period was 3 weeks. Test results were as follows:

Test substance animal A. rat B. rat C. rat C. mouse F. mouse P. mouse Q mouse

LD ₅₀
(mg / kg)

> 4000> 4000> 4000

> 12500 ·)

> 12500 ·)

> 12 500)

> 12 500)

*) According to Spearman-Kärber.

If doses higher than 12,500 mg / kg were administered, apathy, accelerated breathing and lust for pleasure, mortalities, persisted for several hours however, no pathological and anatomical changes were found after weaning.

In contrast, the LD is ₅ O value of clofibrate (p-Chlorphenoxyisobuttersäureäthylester) 1150 mg / kg.

Anti-lipemic efficacy

The antilipemic effectiveness of substances B, C, O, P according to the invention according to Table I and of clofibrate as a reference substance was used in a three-stage model experiment on normolipemic SPF Wistar rats (10 animals / group each), by oral administration over a test period of 14 days examined.

Blood samples were used 24 hours after the last application of the substances or the vehicle Determination of serum cholesterol and triglyceride levels taken.

In the first series of tests, 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 ran parallel to the first Series was carried out, the animals received a high-cholesterol diet (fat diet 1; according to Berger et al, Proc. Soc. Ex. Biol. [1969], 132, 293).

In a third series of experiments, the effectiveness was tested on young male rats (weight 80-90 g)

10 identified those with a cholesterol and butter-enriched 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 Il

Antilipemic effectiveness on the rough (p. O.) Below Normal diet:

Test dose
group tion
mg% F. final value
Cholest.
mg% Changes
tion Final value
Triglyz. Ver
changes
tion Control - 76.9 - 123.8 - 250 / * t, U
75.5 - J ₁ I /
-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 period
space. of the trial time

Table III

Anti-lipemic efficacy on hypercholesterolemic fat diet the fat diet 2

as well as cholesterol and butter creme

Test group fat diet I

control
B.

Dosing final value
Cholest.

mg / kg

100
250

100

100
250

100
250

Changes
tion

mg

358.6

343.2
395.7 ·)

351.6
362.4

Clofibrate 250

1000 ')

ρ <0.05.

p <0.01.

ρ <0.001.

3 out of 10 animals died.

- 4.3
+ 103

- 2.0

+ U

381.9 + 6.5

458.2 *) +27.8

3473 - 3.0

245.4 '") -31.6

Endwen Triglyz.

Change

86.4

84.7 70.0 *)

91.6 124.0

96.7 12U)

75.6 1203-2.0
-19.0

+ 6.0
+ 43.5

+ 11.9
+403

-12.5
+ 39.2

Fat diet 2

E mi worth
Cholest.

mg%

Changes
tion

Final value Ver Trigly /. modification

123.1

112.0

135.7

-9.0 126.9

- 6.5

1333

+ 8.3 107.7 ») -20.6

If one compares the test results for compounds B, C, O and P with those of the clofibrate, the result is 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 therapeutics both with and without additional dietary measures for the treatment of diseases with increased serum cholesterol and triglyceride levels, such as B.> Atherosclerosis or special metabolic disorders.

Claims (1)

Patent claims: 1. 2-Amino-4-phenylethylamino-phenoxymethyl-1,3,5-triazines of the general formula (I) in the a halogen atom or the trifluoromethyl group is,