DE2263110A1 - NEW 1,3,5 - TRIAZINES AND THE METHOD OF MANUFACTURING THEM - Google Patents

Description

PATENT LAWYERS

DR. ING. A. VAN DERWERTH DR. FRANZ LEDERER Sl HAMBURG 90 8 MUNICH BO WlLITOKrE * ITR. Sl · Tit. (04 11 »77 OB dl · LUCUE-GRAHN-tTR. 30 · PART. 10» I Il 47 39 47

Munich »December 22, 1972

Ludwig Merckle KG, chem.pharnu factory ,, Blaubeuren

New l _ff 3, -5 - triazines and processes for their

Manufacturing

The invention "relates to new 1,3,5-triazines in general Formula (I)

in which X is a halogen atom or the trifluoromethyl group, R ₁ and Rp are identical or different and represent hydrogen atoms or aliphatic straight-chain or branched hydrocarbon radicals with 1 to 5 carbon atoms and R_ represents a hydrogen atom, a C ₁ C alkanecarboxylic acid radical or a halophenoxyalkanecarboxylic acid radical . .

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Preferred halogen atoms are chlorine and fluorine. Chlorine becomes special 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 groups, as well as branched pentyl groups. Alkyl radicals with 1 to 3 carbon atoms are preferred. The methyl group is particularly preferred.

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

Preferred halophenoxyalkanecarboxylic acid radicals have 1 to 5, preferably 1 to 3 »carbon atoms in the alkanecarboxylic acid radical. Specific Examples of suitable alkanecarboxylic acid radicals are mentioned above. The 2- (p-Qilorpbencjxy) - propionyl group is particularly preferred,

Those triazines of the general formula (I) that have a free Possess amino group, form salts with 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 also relates to a process for the preparation of the triazines of the general formula (I), which is characterized is that you have a phenoxyalkanecarboxylic acid of the general formula (II)

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Cn)

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

CH ₂ OH ₂ NH-C-NH-C -

H H-

NH NH

converts, and optionally the amino group in the 2-position des Triazines with an alkanecarboxylic acid or halophenoxyalkanecarboxylic acid or a reactive derivative of these acids per se esterified in a known manner.

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

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

Surprisingly, the production according to the invention succeeds Triazines particularly easy if you use the phenylethyl

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biguanide base with an allyl ester of phenoxyalkanecarboxylic acid in an inert solvent such as Ohloroform, in the absence of a catalyst.

If R ₁ and R «are hydrogen atoms, the reaction at room temperature is complete after a few hours. If R ₁ 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 halides or acid anhydride is omitted, whereby a very simplified and gentle 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 which exceeds the well-known antilipaemic clofibrate (ethyl p-chlorophenoxyisobutyrate) many times over. They are characterized by good versatility. tolerable and low toxicity. _{The LD 5Q} value determined in SPF rats is over 4 g / kg on oral administration of the triazines prepared in Examples 1, 2 and 3.

Surprisingly, it was also found that at extremely low Dosage the triazines of the invention can potentiate the therapeutic effects of clofibrate.

The medicaments of the invention contain one or more triazines of the general formula (I) as an active ingredient. The application is preferably carried out orally, e.g. in the form of capsules or tablets, the customary pharmaceutical excipients where appropriate and tools included.

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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 hydrochloride by alkalization, is dissolved in 200 ml of chloroform with gentle warming and filtered. 21.4 g (0.1 mol) of ethyl p-chlorophenoxyacetate are added to the filtrate and the mixture is stirred at room temperature for 6 hours. It starts after about 2 hours. to precipitate the reaction product from the previously clear solution. The crystals are filtered off with suction, washed with a little chloroform and dried. That so. received. Crude product (14.4 g) is suspended in 200 ml of water with stirring and, after standing overnight, is filtered off with suction. 13.3 g (82.1% of theory) of 2-amino-4- (2-phenylethyl-. Amino} -6- (p-chlorophenoxymethyl) -1,3,5-triazine are obtained as colorless crystals Melting point 190-92 ° C. · A sample crystallized from ethanol shows a melting point of 193-95 ° C.

Elemental analysis t

(355.8)

Ber, Gef.

C HN Cl

60.76 5.10 19.69 9.97 60.74 5.14 19.93 9.69

IR (KBr): 3510 / cm (^ NH ₂ ) 3260, 3120 / cm C-WH)

. 1660, 164O / cm (£ nh ₂ ) 1572 (JPRing) 1242, 1010 / cm (COC) 828, 809, 750, 705 / cm

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-5-

Example 2 t

24.1 g (0.1 Hol) Phenyläthylbiguanid hydrochloride are dissolved in water, made alkaline with sodium hydroxide solution and with
200 ml of chloroform extracted in portions. The chloroform solution, dried with sodium sulfate and filtered, is mixed with 30.3 g (0.1 mol) of 2- (p-chlorophenoxy) propionic anhydride and heated under reflux for 1 hour.
The washed with dilute sodium hydroxide solution and water
The chloroform phase is evaporated on a rotary evaporator and the distillation residue is crystallized from aqueous isopropanol. 19.0 g (53% of theory)
2-Amino-4- (2-phenylethylamino) -6- £ 2- (p-chlorophenoxy) ethyl / 1,3,5-triazine with a melting point of 152 ° -54 ° C. was obtained. Recrystallization from a little ethanol gives colorless needles with a melting point of 154 C.

Elemental analysis:

C H N 'Cl

C ₁₉ H ₂₀ ClN ₅ O Calculated: 61.70 5.45 18.94 9.58

(369.86) Found: 61.65 5.50 18.74 10.31

IR (KBr): 3510 / cm (ΓΝΗ ₂ ); 3280, 3125 / cm (-NH)

1655 ("TnH ₂ ) 1605, 1575 / cm OfRfcBg); 1238,
1015 / cm (COC) 832, 825 / cm.

NMR (CDC1 ₃ / 6O MHz): (T = 1.68 (d, 3H); S »2.96 (m, 2H) i

f- 3.76 (in; 2H) i £ «4.93 (d, lH)

Total proton number; 20 H.

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Example 3:

. 2O ₁ 5 g (0.1 mole) Phenyläthylbiguanid base are dissolved with the addition of 50.0 g (0.2 koi) p-chloro ^ phenoxyisobuttersäureäthylester in 100 ml of ethanol and heated under reflux for 5 hours · The solution is evaporated and the excess of ethyl p-chlorophenoxyisobutyrate is gently distilled off in an oil pump vacuum. The residue is crystallized from aqueous ethanol, with 11.5 g (30 % of theory) of 2-amino-4- (2-phenyl ethylamino) -6- | _2- (p-chlorophenoxyJ-isÖpropyrj'-l , 3,5-triaziri with a melting point of 141-43 ° C.

Elemental analysis;

CHN Cl C ₂₀ H ₂₂ ClN ₅ O. Calc .: 62.58 5.77 18.24 9.23 (383.9). Found: 62.61 5.83, 18.23, 9.29

IR (KBr): 3520 / cm (VNH ₂ ) 3280, 3145 / cm (NH) 1615 / cm 1250, 1015 / cm (COC); 832.7O2 / cm

NMR (CDC1 ₃ / 6O MHz): (T = 1.69 (s, 6H) 5 f = 2.95 (m, 2H);

J = 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 dissolved in 100 ml Suspended toluene and, after adding 9.6 g of phosphorus oxychloride, heated under reflux for 4 hours * The reaction solution is stirred up with dilute sodium hydroxide solution and the crystals obtained are filtered off with suction.

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The crystals are crystallized from aqueous ethanol, 16.7 g (47% of theory) of 2-amino-4- (2-phenylethylamino) -6- (p-chlorophenoxymethyl) -1, 3,5-triazine with a melting point of 189-91 ° C.

Example 5;

18.5 g (0.05 mol) of 2-amino-4- (2-phenylethylamino) -6- £ 2- (p-chlorophenoxy) ethyl-1,3,5-triazine, melting point 152-154 ° C in 27.7 g (0.25 Hol) of acetic anhydride are refluxed for 6 hours and the excess Acetic anhydride distilled off in vacuo. The residue is crystallized from isopropanol, whereby 12.4 g (60.5% of theory) of 2-acetylamino-4- (2-phenylethylamino-6-J_2- (p-chlorophenoxy) -ethyIJ-1,3,5-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 100); 1580, 1545, 1460, 1190, 830 / cm.

Example 6; ^:

18.5 g (0.05 mol) of 2-amino-4- (2-phenyl ethylamino) -6- | j2- (p-chlorophenoxy) -ethyl-1,3,5-triazine and 20.8 g (0.06 KoI) 2- (p ~ chlorophenoxy) propionic anhydride are in 200 ml Xylene heated under reflux for 6 hours. 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.

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-8th-

7.7 g (28% of theory) 2 -! ^ - (ppropiQnylamino'j - ^ - (2-phenylethylamino) -6-1 ~ 2- (p-chlorophenoxy) -ethyl-1,3,5-triazine obtained from melting point 170-74 ° C.

The constitution results from the lack of the band typical for the triazine used at 35GO / cm, as well as the appearance of a carbonyl band at 1690 / cm.

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

Example 7; *. .

9.35 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 recrystallized from ethanol with the addition of water. .. There are -7.6 g (47 % . Th.) 2-Amino-4- (2-phenylethylamino) -6- (o-chlorophenoxymethyl) -1, 3j 5-triazine with a melting point of 10-3-1O5 ° C received.

IR (KBr): 3498 / cm (X ¹ NH ₂ ); 3260 / cm C-NH); 1660, 1645 / cm

(InH ₂ ) 1242, 1008 / cm (COC); 808, 745, 702 / cm.

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- ίο -

Example B;

9.35 g (45.5 mol) of phenylethylbiguanide base and 27.5 g (0.1 mol) of 2- (m-trifluoromethylplienoxy) -2-methylpropionic acid ethyl ester in 250 ml of chloroform are heated under reflux for 5 hours. After the solution has been evaporated, the excess ethyl ester is distilled off in an oil pump vacuum. The distillation residue is redissolved in chloroform and washed successively with dilute sodium hydroxide solution, dilute hydrochloric acid and water. After evaporation of the solution, H ₁ G g (62 %) of 2-amino-4- (2-phenylethylamino) -6- [2- (m-trifluoromethylphenoxy) isopropyl] -1,3,5-triazine remain as a yellowish oil which could not be brought to crystallization. According to TLC, "the product is still contaminated with about 2% phenylethylbiguanide.

IR (film): 3510 / cm (NH ₂ ); 3280, 3135 / cm (NH) "; 1650 / cm (

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Claims (10)

Claims 1. . 1,3f5-triazines of the general formula (I) ^r (I) in the X is a halogen atom or the trifluoromethyl group, R ₁ and R _{2 are} identical or different and are hydrogen atoms or aliphatic, straight-chain or branched hydrocarbon radicals with 1 to 5 carbon atoms, and IU is a hydrogen atom, a C ^ c -alkanecarboxylic acid radical. or represents a halophenoxyalkanecarboxylic acid residue. 2x2-amino-4- (2-phenylethylamino) -6- (p-chlorophenoxymethyl) -1,3,5-triazine. 3. 2-Amino-4- (2 * phenylethylamino) -6- / 2- (p-chlorophenoxy) - - ethyl, 7-1,3,5-triazine. 4. 2-Amino-4- (2-phenylethylamino) -6 - / "2- (p-chlorophenoxy) -isopropyl / -1,3» 5-triazine. 5. 2-Acetylamino-4- (2-phenylethylamino) -6 - / "2- (p-chlorophenoxy) ethyl / -1,3,5-triazine. 409828 / Ί065 6. 2- / 2- (p-chlorophenoxy) propionylamine q / ^ - (2-phenylethylamino) -6 - / * 2- (p-chlorophenoxy) ethyl / -1,3,5-triazine. 7. 2-Amino-4- (2-phenylethylamino) -6- (o-chlorophenoxymethyl) -1,3f5-triazine. 8. 2-Amino-4- (2-phenylethylamino) -6- / 2- (m-trifluoromethylphenoxy) -isopropyl7-1,3,5-triazine. 9. Process for the preparation of the triazines according to claim 1, characterized in that one is a phenoxyalkanecarboxylic acid of the general formula (II) (II) in which X, R ₁ and R _{2 have} the aforementioned meaning, or a reactive derivative of the phenoxyalkanecarboxylic acid of the formula (II) _; with phenylethyl biguanide of the formula v \ // - CH ₀ CH ₀ NH-C -NH-C-NH V // * ■ £ it ti
NH NH converts, and optionally the amino group in the 2-position des Triazines with an alkanecarboxylic acid or halophenoxyalkanecarboxylic acid or a reactive derivative of these acids is esterified in a manner known per se. 10. Medicines, characterized by a content of one or more compounds according to claims 1 to 8. 409828/1065