DE1545753C - Unsubstituted triazines and processes for their preparation - Google Patents
Unsubstituted triazines and processes for their preparationInfo
- Publication number
- DE1545753C DE1545753C DE1545753C DE 1545753 C DE1545753 C DE 1545753C DE 1545753 C DE1545753 C DE 1545753C
- Authority
- DE
- Germany
- Prior art keywords
- triazines
- preparation
- trichloromethyl
- processes
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000002360 preparation method Methods 0.000 title claims description 3
- 238000000034 method Methods 0.000 title claims 2
- 150000003918 triazines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 10
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-Triazine Chemical class C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 229960002895 Phenylbutazone Drugs 0.000 description 6
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000003110 anti-inflammatory Effects 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 229920000742 Cotton Polymers 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- 125000006414 CCl Chemical group ClC* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- 210000002683 Foot Anatomy 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 description 1
- 206010072736 Rheumatic disease Diseases 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003501 anti-edematous Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000002062 proliferating Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000552 rheumatic Effects 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 231100000730 tolerability Toxicity 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- -1 triazine ester Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
Die Erfindung betrifft trisubstituierte s-Triazine der allgemeinen Formel IThe invention relates to trisubstituted s-triazines of the general formula I.
N \
N
. J s
. NC.
. J s
. N
//
CH3 -,C-OH
CH 3 -,
·. ■ N ZC
·. ■ N
(I)(I)
Z-CZ-C
N CH,N CH,
C —C —O —C —R (II)C —C —O —C —R (II)
CH,CH,
wird. Den in Wasser unlöslichen Anteil'nimmt man mit Methylerichlorid auf und engt diese Lösung nach dem Neutralwaschen ein. Der Rückstand wird mit Wasser verrieben, wobei er kristallisiert. Die Ausbeute an 2-[«-Hydroxy-rx-methyl-äthyl];4-rnprpholino-6-trichlormethyl-l,3,5-triazin beträgt 18 g, das ist 43,5% der Theorie; Fp. 96 bis 98°C.will. The water-insoluble fraction is taken up with methylene chloride and this solution is then concentrated neutral washing. The residue is triturated with water, whereupon it crystallizes. The yield to 2 - [«- Hydroxy-rx-methyl-ethyl]; 4-rnprpholino-6-trichloromethyl-1,3,5-triazine is 18 g, that is 43.5% of theory; Mp 96 to 98 ° C.
3°3 °
in der Y und Z die oben angegebene Bedeutung besitzen und R einen Alkyl- oder Alkyloxyrest mit 1 bis 6 C-Ätomen, Aryl- oder Aryloxyrest bedeutet, in Gegenwart eines mit Wasser mischbaren organischen Lösungsmittels und etwa molaren Mengen Bariumhydroxid bei einer Temperatur zwischen etwa 0° C und etwa der Siedetemperatur des Lösungsmittels verseift.in which Y and Z have the meaning given above and R is an alkyl or alkyloxy radical 1 to 6 carbon atoms, aryl or aryloxy radical means in the presence of an organic which is miscible with water Solvent and about molar amounts of barium hydroxide at a temperature between about 0 ° C and about the boiling point of the solvent saponified.
Die erfindungsgemäßen Verbindungen können als analgetisch und antiphlogistisch wirksame Mittel verwendet werden.The compounds according to the invention can be used as analgesic and anti-inflammatory agents be used.
Die Herstellung der erfindungsgemäßen Verbindungen durch Hydrolyse der Ester der allgemeinen Formel II wird insbesondere in Gegenwart eines niederen Alkohols, vorzugsweise Methanol, durchgeführt. Die Reaktionstemperatur wird vorzugsweise auf 50 bis 700C gehalten.The preparation of the compounds according to the invention by hydrolysis of the esters of the general formula II is carried out in particular in the presence of a lower alcohol, preferably methanol. The reaction temperature is preferably maintained at 50 to 70 0 C.
■ B e i s ρ i e 1 1■ B e i s ρ i e 1 1
50 g 2-[«-(Carbäthoxyoxy)-«-methyl-äthyl]-4-morpholino - 6 - trichlormethyl -1,3,5 - triazin werden in 300 ml Methanol gelöst und zum Sieden erhitzt. 42 g Ba(OH)2-8H2O werden heiß in 400 ml Methanol gelöst, vom Carbonat abfiltriert und innerhalb von 3 Stunden unter ständigem Sieden zur Lösung des Triazinesters zugegeben. Die zu Beginn des Zutropfens klare Lösung wird im Verlauf der Verseifung milchig trübe. Man engt ohne vom Feststoff abzutrennen das Reaktionsgemisch ein und verrührt den Rückstand mit verdünnter HCl, wobei CO2 frei50 g of 2 - [«- (carbethoxyoxy) -« - methyl-ethyl] -4-morpholino-6-trichloromethyl-1,3,5-triazine are dissolved in 300 ml of methanol and heated to the boil. 42 g of Ba (OH) 2 -8H 2 O are dissolved hot in 400 ml of methanol, the carbonate is filtered off and added to the solution of the triazine ester over the course of 3 hours with constant boiling. The solution, which is clear at the beginning of the dropwise addition, becomes milky cloudy in the course of the saponification. The reaction mixture is concentrated without separating from the solid, and the residue is stirred with dilute HCl, CO 2 being liberated
in der Y eine Trichlormethyl- oder Äthylaminogruppe und Z einen Morpholino- oder Piperazinorest bedeutet. in which Y is a trichloromethyl or ethylamino group and Z is a morpholino or piperazino radical.
Die erfindungsgemäßen Verbindungen werden dadurch hergestellt, daß man in an sich bekannter Weise eine Verbindung der allgemeinen Formel IIThe compounds according to the invention are prepared by in a manner known per se a compound of the general formula II
20 Y "· 20 Y "·
I CN
I.
. -Λ N
. -Λ
N
/
CI.
N
/
C.
B e i s ρ i e 1 2B e i s ρ i e 1 2
114 g 2-[ti- Carbomethoxyoxy - a - methyl - äthyl]-4-morpholino-6-trichlormethyl-s-triazin (Fp. 90 bis 950C) werden in 500 ml Methanol heiß gelöst und mit einer Lösung von 90 g Ba(OH)2 · 8 H2O in 750 ml Methanol innerhalb von 30 Minuten versetzt und IV2 Stunden unter Rückfluß gerührt. Die Aufarbeitung erfolgt wie im Beispiel 1 beschrieben.114 g of 2- [ti- Carbomethoxyoxy - a - methyl - ethyl] -4-morpholino-6-trichloromethyl-s-triazine (mp 90 to 95 0 C.) Are dissolved hot in 500 ml of methanol and treated with a solution of 90 g Ba (OH) 2 · 8 H 2 O in 750 ml of methanol was added over the course of 30 minutes and the mixture was stirred under reflux for 2 hours. Working up is carried out as described in Example 1.
Ausbeute: 51 g von 2-[«-Hydroxy-«-methyl-äthyl]-4-morpholino-6-trichlormethyl-s-triazin, das ist 52% der Theorie; Fp. 96 bis 98° C.Yield: 51 g of 2 - [«- Hydroxy -« - methyl-ethyl] -4-morpholino-6-trichloromethyl-s-triazine, that's 52% of theory; Mp. 96 to 98 ° C.
TestergebnisseTest results
Die pharmakologische Wirksamkeit, therapeutische Breite und akute Toxizität der Verbindungen 2-[«-Hydroxy - a -methyl - äthyl] - 4 - morpholjno - 6 - trichlormethyl -s-triazin (I) und 2-[u-Hydroxy-u-methyläthyl] - 4 - äthylamino - 6 - piperazino - s - triazin (II) wurden mit Phenylbutazon verglichen.The pharmacological effectiveness, therapeutic range and acute toxicity of the compounds 2 - [«- Hydroxy - a -methyl - ethyl] - 4 - morpholino - 6 - trichloromethyl-s-triazine (I) and 2- [u-hydroxy-u-methylethyl ] - 4 - ethylamino - 6 - piperazino - s - triazine (II) were compared with phenylbutazone.
Die antiphlogistische Wirkung wurde am Carrageenin-ödem der Rattenpfote nach der Methode von D omen j oz und Mitarbeitern, Arch, exper. Pharm. Path., 230, 325 (1957), bestimmt. Die antiphlogistische Wirkung ist als Ödemhemmung in Prozent gegenüber der unbehandelten Kontrollgruppe und als ED50 in mg/kg angegeben (ED50 = Dosis, die eine Ödemhemmung von 50% bedingt).The anti-inflammatory effect was determined on the carrageenin edema of the rat paw by the method of Domen j oz and coworkers, Arch, exper. Pharm. Path., 230, 325 (1957). The anti-inflammatory effect is given as edema inhibition in percent compared to the untreated control group and as ED 50 in mg / kg (ED 50 = dose which causes edema inhibition of 50%).
Aus dem Verhältnis der toxischen Dosis (LD50 in mg/kg) zur ED50 ergibt sich die therapeutische Breite als Maß für die Verträglichkeit der Substanz.The ratio of the toxic dose (LD 50 in mg / kg) to the ED 50 gives the therapeutic range as a measure of the tolerability of the substance.
. Die Toxizitätsprüfung wurde an der Ratte durch Bestimmung der akuten Toxizität (= LD50 in mg/kg) nach Miller und Tainter, Proc. Coc. Exper. Biol. and Med., 57, 261 (1944), durchgeführt. Beobachtungszeit: 24 Stunden.. The toxicity test was carried out on the rat by determining the acute toxicity (= LD 50 in mg / kg) according to Miller and Tainter, Proc. Coc. Exper. Biol. And Med., 57, 261 (1944). Observation time: 24 hours.
Alle Versuche wurden bei oraler Applikation durchgeführt. All experiments were carried out with oral administration.
Die Ergebnisse sind in der nachfolgenden Tabelle wiedergegeben.The results are given in the table below.
I (F. 96 bis 98"C)
H(F. 88 bis 92"C)
Phenylbutazon ...I (F. 96 to 98 "C)
H (F. 88 to 92 "C)
Phenylbutazone ...
üdemhemmung in % bei 30 mg/kgoem inhibition in% at 30 mg / kg
57
50
4757
50
47
ED30 in mg/kgED 30 in mg / kg
11,6 3011.6 30
75 Therapeutische Breite75 Therapeutic breadth
66
30
7,066
30th
7.0
770 ±136
etwa 1000
530 ± 59770 ± 136
about 1000
530 ± 59
Die Tabelle zeigt, daß die erfindungsgemäßen Verbindungen eine stärkere ödemhemmende Wirkung als Phenylbutazon aufweisen. Ebenso liegen die ED50 und die therapeutische Breite · wesentlich günstiger, . wodurch eine überlegene Verträglichkeit der neuen Verbindungen verdeutlicht wird. .The table shows that the compounds according to the invention have a stronger anti-edema effect than phenylbutazone. The ED 50 and the therapeutic range are also much more favorable,. whereby a superior compatibility of the new compounds is made clear. .
Die Verbindung I wurde außerdem im Cottonpellet-Test nach Meier, Schuler und Desaulles, Experienta, 6 (1950), mit Phenylbutazon verglichen. Die erhaltenen Ergebnisse sind in der nachfolgenden Tabelle wiedergegeben. Die Dosierung betrug bei beiden Substanzen 50 mg/kg oral täglich über 4 Tage. Die antiphlogistische Wirkung ist als Proliferationshemmung in Prozent gegenüber der unbehandelten Kontrollgruppe angegeben (%), η bedeutet die Anzahl der eingesetzten Tiere.Compound I was also compared with phenylbutazone in the cotton pellet test according to Meier, Schuler and Desaulles, Experienta, 6 (1950). The results obtained are shown in the table below. The dose for both substances was 50 mg / kg orally daily for 4 days. The anti-inflammatory effect is given as an inhibition of proliferation in percent compared to the untreated control group (%), η means the number of animals used.
Phenylbutazon ,Phenylbutazone,
ProliferationshemmungInhibition of proliferation
25
1625th
16
20 3020th 30th
Die Tabelle zeigt, daß die Verbindung 1 im Cottonpellet-Test zweimal stärker antiphlogistisch wirksam ist als Phenylbutazon. Da dieser Test als Modell einer proliferatigen Entzündung unter anderem auch chronische Erkrankungen des rheumatischen Formenkreises nachahmt, ist diese Überlegenheit besonders bedeutungsvoll.The table shows that compound 1 in the cotton pellet test is twice as effective as phenylbutazone as anti-inflammatory. As this test as a model a proliferative inflammation including chronic diseases of the rheumatic type that superiority is particularly meaningful.
Claims (2)
Formel I1. Trisubstituted
Formula I.
y s
N
I C.
y s
N
I.
N\
N
Z-C
\ ,
NI.
ZC
\,
N
/C-
/
C — C — ON CH 3
C - C - O
C-R
O. (II)
CR
O
Family
ID=
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