US3759911A

US3759911A - Triazine derivatives

Info

Publication number: US3759911A
Application number: US00153395A
Authority: US
Inventors: T Irikura; F Morinaga; K Higo; A Maeda; Y Abe; K Okamura
Original assignee: Kyorin Pharmaceutical Co Ltd
Current assignee: Kyorin Pharmaceutical Co Ltd
Priority date: 1968-04-10
Filing date: 1971-06-15
Publication date: 1973-09-18
Anticipated expiration: 1990-09-18
Also published as: GB1252870A; DE1913154B2; GB1250971A; DE1907589A1; FR2005902A1; US3758471A; BE726947A; DE1907589B2; DE1913154C3; DE1907589C3; FR2005901A1; BE726948A; DE1913154A1

Abstract

S-TRIAZINE DERIVATIVES OF THE FORMULA

2-(C6H5-(CH2)2-NH-),4-NH2,6-R-S-TRIAZINE

WHEREIN R IS PYRROLIDINO, PIPERIDINO, 2-KETOPIPERAZINE-4YL OR NR1R2, R1 BEING HYDROGEN OR STRAIGHT OR BRANCHED ALKYL OF FROM 1-6 CARBON ATOMS AND R2 BEING CYCLOALKYL OR STRAIGHT OR BRANCHED ALKYL OF 1-6 CARBON ATOMS, AND THE ACID ADDITION SALTS OF THE COMPOUND WITH ORGANIC OR INORGANIC ACIDS.

Description

States Patent 3,759,911 a TRIAZINE DERIVATIVES Tsutomu Irikura, Yasno Abe, Kyuya Okamura, Kyoichi Higo, Akitoshi Maeda, and Fnmihiko Morinaga, Tokyo, Japan, assignors to Kyorin Seiyaku Kabnshiki Kaisha, Tokyo, Japan No Drawing. Continuation of abandoned application Ser. No. 808,294, Mar. 18, 1969. This application June 15, 1971, Ser. No. 153,395

Int. Cl. C07d 55/22 US. Cl. 260--249.6 1 Claim ABSTRACT OF THE DISCLOSURE s-Triazine derivatives of the formula wherein R is pyrrolidino, piperidino, 2-ketopiperazine-4- yl or NR R R being hydrogen or straight or branched alkyl of from 1-6 carbon atoms and R being cycloalkyl or straight or branched alkyl of 1-6 carbon atoms, and the acid addition salts of the compound with organic or inorganic acids.

The new compounds exhibit anti-inflammatory and antiatherosclerotic activity.

CROSS-REFERENCE TO PRIOR APPLICATION This is a continuation of application Ser. 808,294, filed on Mar. 18, 1969, now abandoned.

SUMMARY OF THE INVENTION This invention relates to s-triazine derivatives of the formula wherein R is pyrrolidino, piperidino, 2-ketopiperazine-4- yl or NR R R being hydrogen or straight or branched alkyl of from 1-6 carbon atoms and R being cycloalkyl or straight or branched alkyl of from 1-6 carbon atoms. The acid addition salts of the new compounds with organic and inorganic acids, such as hydrochloric acid, maleic acid, tartaric acid, citric acid, and lactic acid are also embraced.

s-Triazine derivatives have been previously disclosed as dye intermediates, but any biological activity of such compounds has not heretofore been reported in the chemical literature.

The inventive compounds can be prepared according to the following reaction scheme:

I RH x \N NHCH CH wherein X is halogen and R has the above meaning.

Activation of the reticnloendothelial system (RES) in 0 Grade of plaque arch...

3,759,911 Patented Sept. 18, 1973 TABLE I Compound of Example No.: Inhibitory percentage 1 216.0 2 123.5 3 142.4 4 101.5 5 219.5 6 107.4 7 110.3 8 173.0 9 168.9

Each value is the average value obtained in testing 5 mice.

Activated RES on mice were induced by administration of typhoid-paratyphoid-vaccine every other day. Typhoidparatyphoid-vaccine was injected intravenously in an amount of 0.1 m1./ animal at the tail vein.

The inhibitory percentage was determined by carbon phagocytosis of RES and calculated relative to a control which is defined as 100.

The inventive compounds were administered, 300- mg./ kg., orally one hour before injection of typhoid-paratyphoid-vaccine.

The correctness of the above assumption and correlation have been established based on the results of the screening and toxicity in case of the Example 1 compound.

The s-triazine derivatives of the present invention exhibit either anti-inflammatory activity or anti-atherosclerotic activity. These activities have been satisfactorily demonstrated in animal tests. For example, 2-amino-4- phenethylamino-G-(Z ketopiperazine-4 yl)-s-triazine (Example 1), when administered orally to rabbits, caused TAB LE II Ilntluenee of the Example 1 Compound on Serum Cholesterol, Cholestrol Content of Aorta and Grade oi Atherosclerotie Plaques of Rabbits which were fed a High Cholesterol Diet for Days] N orma Cholesterol diet group diet Percentage of drug in diet Number of rabbits Serum cholesterol (mg.

percent) 9895:595 1, 216z|=627 1, 887:1:621 Cholesterol content of aorta (mg/wet. g.)...

13.4:b8.3 7.3:l=2.9 l9.9:l=4.9 Cholesterol content of liver (mgJwet. g.) l8. 2:1:5. 5 17. 43:6. 9 23. 5:1;4. 3 2. hi0. 3 3. 2:111. 6 3. 1:1:0. 5 4. 410. 5 O 1. 8:1:1. 0 1. 4:1:1. 1 3. 3:1:0. 6 0 0. 7:1:1. 2 O. 5:1:0. 6 2:1:1. 4 0

Thoracic Abdominal 3 The remarkable inhibitory effect of the Example 1 compound was indicated in the average plaque grade of the aortas and the cholesterol content of the aorta was significantly decreased. In addition, a different experimental group of rabbits received a cholesterol diet for 80 days and then was put on normal diet.

The Example 1 compound in a concentration of 0.1% was introduced at that time into the diet of one group. The control group was fed a normal diet. These animals were then killed at intervals up to 43 days thereafter. The aortas were removed and examined histologicaly with a number of different stains.

The results indicated decreased sudanophilic material and foam cells in the plaques of the group treated with the Example 1 compound, as compared with that of the control group. Fibrous tissue proliferations without sudanophilic material were observed instead and rapid regression was observed in the aortic plaque of the group treated with the Example 1 compound.

The anti-inflammatory activity of the Example 1 compound was demonstrated by the following:

Rats, immunized by repeated injection of bovin serum albumin and adjuvant, were fed orally twice a dose of 150 mg./kg./day of the Example 1 compound. Inhibition of passive cutaneous anaphlaxis reaction was determined by the diflusible method of pigments. A 48% increase in inhibition was observed, as compared with the inhibition observed in the control group.

When 100 mg./kg./day of the Example 1 compound was orally administered to rats immunized by heat killed Tubercli-Bacilli in mineral oil, for 4 days, 24% inhibition of passive cutaneous anaphlaxis reaction was observed, as compared with that of the control group.

When 300 mg./kg. of the Example 1 compound was administered to rats orally, inflammatory edema caused by carrageenin in the paw was about 25% less than the value of the control.

The Example 1 compound has a low toxicity. No mortality occurred in the oral administration of over 20 g./kg. of the Example 1 compound to mice.

Various cortison-inhibitory activities were also observed in the inventive triazine derivatives. Therefore, the inventive compounds are not only pharmacologically useful as an anti-atherosclerotic agent, but they also act as an anti-inflammatory agent in place of steroidal anti-inflammatory agents.

EXAMPLE 1 2-amino-4-phenethylamino-6- Z-ketopiperazine- 4-yl) -s-triaz.ine

Phenethylamine (6.1 g.) is added, with stirring, to a mixture of 2-amino-4,6-dichloro-s-triazine (8.2 g.) in Water (100 ml.). The mixture is slowly heated to reflux temperature and the refluxing temperature is maintained for 2 hours. During this time, sodium carbonate (2.7

g.) is added at such a rate that the reaction mixture remains neutral. After cooling, the product is filtered from the reaction mixture and recrystallized from ethanol to yield 2-amino-4-phenethylamino-6-chloro-s-triazine as white crystals, M.P. 2l4-6 C. The yield is 9.0 g.

The compound (3.7 g.) in water (80 ml.) is added, with stirring, to Z-ketopiperazine (3.0 g.) in water (80 ml.). The reaction mixture is refluxed on a steam bath for 2 hours. Crystals formed are collected by filtration and recrystallized from ethanol to give 2-amino4phenethylamino-6-(2-ketopiperazine-4-yl)-s-triazine as white crystals, M.P. 230 C. The yield is 2.3 g.

Alnalysis.-Calcd. for C15H19N7O (percent): C, 57.49; H, 6.08; N, 31.29. Found (percent): C, 57.62; H, 6,25; N, 30.65.

EXAMPLE 2 2-amino-4-phenethylamino-6-methylamino-s-triazine 40% methylamine (3.9 g.) is added, with stirring, to a mixture of 2-amino-4-phencthylamino-6-chloro-s-triazine (6.2 g.) in water ml.). The mixture is slowly heated to the reflux temperature, and the reflux temperature is maintained for 2 hours. After cooling, the product is filtered from the reaction mixture and recrystallized from acetonitrile to give 2-amino-4-phenethylamino-6-methylamino-s-triazine as white crystals, M.P. 166-167 C.

Analysis.Calcd. for C H N (percent): C, 58.99; H, 6.60; N, 34.40. Found (percent): C, 58.84; H, 6.79; N, 34.22.

EXAMPLE 3 Z-amino-4-phenethylamino-6-pyrrolidinos-triazine maleate Pyrrolidine (3.6 g.) is added, with stirring, to a mixture of 2-amino-4-phenethylamino-6-chloros-triazine 6.2 g.) in water ml.). The mixture is slowly heated to the reflux temperature, and the refluxing temperature is maintained for 2 hours. After cooling, the mixture is extracted with chloroform, and the chloroform solution is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a syrup. The syrup (7.0 g.) is dissolved in methanol (40 ml.) and added to a solution of maleic acid (2.0 g.) in methanol (10 ml.) to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from methanol to give 2-amino 4 phenethylamino-6-pyrrolidino-s-triazine maleate as colorless needles, M.P. 149- 150 C. The yield is 2.1 g.

Analysis.Calcd. for C H N O (percent): C, 56.99; H, 6.04; N, 20.99. Found (percent): C, 56.79; H, 5.90; N, 20.96.

EXAMPLE 4 2-amino-4-phenethylamino-6-piperidinos-triazine maleate Piperidine (4.3 g.) is added, with stirring, to a mixture of 2-amino-4-phenethylamino-6-chloro-s-triazine (6.2 g.) in water (120 ml.). The mixture is slowly heated to the reflux temperature, and the refluxing temperature is maintained for 2 hours. After cooling, the mixture is extracted with chloroform, and the chloroform solution is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a syrup. The syrup (6.0 g.) is dissolved in methanol (40 ml.) and added to a solution of maleic acid (1.7 g.) in methanol 10 ml.) to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from methanol to give 2-amino-4-phenethylamino-G-piperidinos-triazine maleate as white crystals, M.P. 164-166 C. The yield is 3.0 g.

Analysis.-Calcd. for C H N O (percent): C, 57.91; H, 6.32; N, 20.35. Found (percent): C, 58.06; H, 6.41; N, 20.56.

EXAMPLE 5 2-amino-4-phenethylamino-6-ethylaminos-triazine maleate 70% ethylamine (2.9 g.) is added, with stirring, to a mixture of 2-amino-4-phenethylamino-6-chloro-s-triazine (6.2 g.) in water 120 ml.). The mixture is slowly heated to the reflux temperature, and the refluxing temperature is maintained for 2 hours. After cooling, the mixture is extracted with chloroform, the chloroform solution is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a syrup. The syrup (6.2 g.) is dissolved in methanol (20 ml.) and added to a solution of maleic acid (1.7 g.) in methanol (10 ml.) to yield a white precipitate. The precipitate is collected by filtration and recrystallized from methanol to give 2-amino-4-phenethylamino-6-ethylamino-s-triazine maleate as white crystal powder, M.P. l6ll62.5 C. The yield is 0.8 g.

Analysis.--Cald. for C H N O (percent): C, 54.54; H, 5.92; N, 22.45. Found (percent): C, 54.30; H, 6.08; N, 22.56.

EXAMPLE 6 2-amino-4-phenethylamino-6-di n-propylaminos-triazine maleate Di-n-propylamine (5.1 g.) is added, with stirring, to a mixture of 2-amino-4-phenethylamino-6-chloro-striazine (6.2 g.) in water (120 ml.). The mixture is slowly heated to the reflux temperature, and the refluxing temperature is maintained for 2 hours. After cooling, the mixture is extracted with chloroform and the chloroform solution is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a syrup. The syrup (6.8 g.) is dissolved in methanol (30 m1.) and added to a solution of maleic acid (1.7 g.) in methanol. The solvent is evaporated from the mixture to give a residue. The residue is recrystallized from benzene to give 2-amino 4 phenethylamino-6-di-n-propylamino-s-triazine maleate as white crystals, M.P. 118120 C. The yield is 5.0 g.

Analysis.Calcd. for C H N O (percent): C, 58.54; H, 7.02; N, 19.59. Found (percent): C, 58.30; H, 7.13; N, 19.83.

EXAMPLE 7 2-amino-4-phenethylamino-6-di-n-butylaminos-triazine maleate Di-n-butylamine (6.5 g.) is added, With stirring, to a mixture of 2-arnino-4-phenethylamino6-chloro-s-triazine (6.2 g.) in water (120 ml.) The mixture is slowly heated to the reflux temperature, and the refluxing temperature is maintained for 2 hours. After cooling, the mixture is extracted with chloroform, and the chloroform solution is washed with Water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a syrup. The syrup (6.5 g.) is dissolved in methanol (20 ml.) and added to a solution of maleic acid (1.7 g.) in methanol (10 ml.).

The solvent is evaporated from the mixture to give a residue. The residue is recrystallized from acetonitrile to give 2-amino 4 phenethylamino-6-di-n-butylamino-striazine maleate as white crystal powder, M.P. 128-129" C. The yield is 4.2 g.

Analysis.Calcd. for C H N O (percent): C, 60.24; H, 7.47; N, 18.33. Found (percent): C, 60.37; H, 7.64; N,

EXAMPLE 8 2-amino-4-phenethylamino-6-cyclohexylamino-s-triazine maleate Cyclohexylamine (6.1 g.) is added, with stirring, to a mixture of 2-amino-4-phenethylamino-6-chloro-s-triazine (7.5 g.) in water ml.). The mixture is slowly heated to the reflux temperature, and the refluxing temperature is maintained for 3 hours. After cooling, the mixture is extracted with benzene and the benzene solution is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a syrup. The syrup (3.1 g.) is dissolved in methanol (50 ml.) and added to a solution of maleic acid (1.1 g.) in methanol 30 ml.) to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from methanol to give 2 amino-4-phenetliylamino-6-cyclohexylamino-striazine maleate as white crystals, M.P. C. (dec.). The yield is 1 g.

Analysis.-Calcd. for C H N O (percent): C, 58.86; H, 6.59; N, 19.62. Found (percent): C, 58.76; H, 6.59; N, 19.25.

EXAMPLE 9 2-amino-4-phenethylamino-6-n-hexylamino-s-triazine maleate n-Hexylamine (6.1 g.) is added, with stirring, to a mixture of 2-amino-4-phenethylamino-6-chloro-s-triazine (7.5 g.) in water (200 ml.). The mixture is slowly heated to the reflux temperature, and the refluxing temperature is maintained for 3 hours. After cooling, the mixture is extracted with benzene, and the benzene solution is Washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a syrup. The syrup (8.0 g.) is dissolved in methanol (50 ml.) and added to a solution of maleic acid (2.9 g.) in methanol (30 ml.) to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from methanol to give 2 amino-4-phenethylamino-6-n-hexylamino-s-triazine maleate as white crystals, M.P. 139-l42 C. The yield is 0.7 g.

Analysis.--Calcd. for C H N O (percent): C, 58.59; H, 7.02; N, 19.52. Found (percent): C, 58.56; H, 7.00; N, 19.74.

What is claimed is:

1. 2 amino-4-phenethylamino-6-(2-ketopiperazine-4- yl)-s-triazine.

References Cited UNITED STATES PATENTS 2,909,421 10/1959 Gysin et a1 260249.6 X

JOHN M. FORD, Primary Examiner US. Cl. X.R. 424249 UNITED STATES PATENT OFFICE CERTIFICATE OF ORRECTION Patent No. 3,759 Dated September 18 1973 lnventofls) Tsutomu Irikura et a1 7 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the heading of the patent, insert: -Claims Priority, applications Japan April '10 1968 No. SHO 43-23905 June 28, 1968, 'NQ. SHO4344996-- Signed and sealed this 25th day of December 1973.

(SEAL) Atte st;

EDWARD M.FLETCHER ,JR. i RENE D. TEGTMEYER Attesting Officer Acting Commissioner of Patents uscoMM-oc scan-Pea FORM PO-1050 (10-69) u.s. eovznumam PRINTING orncz: lsu o-sss-su,