US3758471A - Triazine derivatives - Google Patents

Triazine derivatives Download PDF

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US3758471A
US3758471A US00153396A US3758471DA US3758471A US 3758471 A US3758471 A US 3758471A US 00153396 A US00153396 A US 00153396A US 3758471D A US3758471D A US 3758471DA US 3758471 A US3758471 A US 3758471A
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percent
triazine
compound
straight
amino
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A Maeda
F Morinaga
K Okamura
K Higo
T Irikura
Y Abe
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Kyorin Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C07D251/70—Other substituted melamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K31/00—Actuating devices; Operating means; Releasing devices
    • F16K31/12—Actuating devices; Operating means; Releasing devices actuated by fluid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01L—MEASURING FORCE, STRESS, TORQUE, WORK, MECHANICAL POWER, MECHANICAL EFFICIENCY, OR FLUID PRESSURE
    • G01L11/00—Measuring steady or quasi-steady pressure of a fluid or a fluent solid material by means not provided for in group G01L7/00 or G01L9/00

Definitions

  • R stands for amino, aralkylamino, pyrrolidino, piperidino, 2-ketopiperazine-4-y1, cyclohexylamino or straight or branched hexylamino;
  • R stands for straight or branched alkyl of from 1-6 carbon atoms, pyrrolidino, piperidino, Z-ketopiperazine- 4-yl or NR R in which R, is hydrogen or straight or branched alkyl of from 1-6 carbon atoms and R is straight or branched alkyl with from 1-6 carbon atoms, with the proviso that (a) when R is phenethylamino, R is amino and R is straight or branched alkyl of from 26 carbon atoms;
  • R when R is aralkylamino, pyrrolidino, piperidino or 2-ketopiperazine-4-yl, R is the same or one of said groups and R is straight or branched alkyl of from 1-6 carbon atoms;
  • R is cyclohexylamino or straight or branched hexylamino, R is the same or one of said groups and R is straight or branched alkyl of from 1-6 carbon atoms;
  • R when R is cyclohexylamino, R is amino and R is pyrrolidino, piperidino, 2-ketopiperazine-4-yl or NR R wherein R and R have the above meaning.
  • the invention relates to s-triazine derivatives of the formula N F i k a wherem R stands for phenethylamino, aralkylamino, pyrrolidino, piperidino, 2-ketopiperazine-4-y1, cyclohexylamino or straight or branched hexylamino;
  • R stands for amino, aralkylamino, pyrrolidino, piperidino, 2-ketopiperazine-4-yl, cyclohexylamino or straight or branched hexylamino;
  • R stands for straight or branched alkyl of from 1-6 carbon atoms, pyrrolidino, piperidino, Z-ketopiperazine- 4-yl or NR R in which R is hydrogen or straight or branched alkyl of from 1-6 carbon atoms and R is straight or branched alkyl with from 1-6 carbon atoms, with the proviso that (a) when R is phenethylarnino, R is amino and R is straight or branched alkyl of from 2-6 carbon atoms;
  • R when R is aralkylamino, pyrrolidino, piperidino or 2-ketopiperazine-4-yl, R is the same or one of said groups and R is straight or branched alkyl of from 1-6 carbon atoms;
  • R when R is cyclohexylamino or straight or branched hexylamino, R is the same or one of said groups and R is straight or branched alkyl of from 1-6 carbon atoms;
  • R when R is cyclohexylamino, R is amino and R is pyrrolidino, piperidino, 2-ketopiperazine-4-y1 or NR R wherein R and R have the above meaning.
  • the invention also embraces the acid addition salts of the compounds with organic or inorganic acids such as hydrochloric acid, maleic acid, tartaric acid, citric acid and lactic acid.
  • RES reticuloendothelial system
  • the s-triazine derivatives of the present invention exhibit anti-inflammatory and/ or anti-atherosclerotic activity. Further, various cortison-like or oortison-inhibitory activities have also been observed in the novel s-tri azine derivatives.
  • the inventive compounds are therefore not only pharmacologically useful as anti-atherosiclerotic agents, but they are also anti-inflammatory agents which may replace steroidal anti-inflammatory agents.
  • the compounds of the present invention can be prepared by two processes which are represented by the following schemes:
  • X is amino or alkyl and Y and Z are the same or different amino radicals.
  • Wis phenethylamino R is straight or branched alkyl of from 26 carbon atoms and R is lower alkyl.
  • Example 1.2-methyl-4,6-diphenethylamino-s-triazine A solution of phenethylamine (4.8 g.) in chloroform (20 ml.) is added in dropwise manner and under cooling to a solution of 2-methyl-4,6-dichloro-s-triazine (3.2 g.) in chloroform (80 ml.). A solution of potassium icarbonate (8.2 g.) in water (10 m1.) is also added to the reaction mixture. After completing the addition, stirring is continued for some time. The chloroform solution is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a crystalline precipitate. The precipitate is recrystallized from ethanol to yield 2-methyl-4,6-diphenethylamino-s-triazine as colorless crystals, M.P. 213-214 C. The yield is 1.0 g.
  • Example 3 -2-methyl-4,6-dicyclohexylamino-s-triazine Cyclohexylamine (8.0 g.) is added, with stirring, to a mixture of 2-methyl-4,6-dichloro-s-triazine (3.2 g.) in Water (100 ml.). The mixture is slowly heated to reflux, and the refluxing temperature is maintained for 2 hours. After cooling, the product is collected by filtration and recrystallized from ethyl acetate to give 2-methyl-4,6-dicyclohexylamino-s-triazine as colorless needles, M.P. 187- 189 C. The yield is 3.7 g.
  • Example 4.2-n-butyl-4,6-dicyclohexylamino-s-triazine The compound is obtained by following the same process as in Example 3, except that 2-n-butyl-4,6-dichloro-striazine (4.2 g.) is employed instead of 2-methyl-4,6-dichloro-s-triazine. Recrystallization from n-hexane yields 3.0 g. of the compound, M.P. l36137 C.
  • Example 5.2-methyl-4,6-dipyrrolidino-s-triazine The compound is obtained by following the same process as in Example 1. Recrystallization from petroleum ether yields 1.0 g. of the compound, M.P. 83-85 C.
  • Example 6.2-methyl-4,6-di(2-ketopiperazine- 4-yl)-s-triazine The compound is obtained by following the same process as in Example 2. Recrystallization from ethanol yields 1.0 g. of the compound, M.P. 303 C. (dec.).
  • Example 7.2-methyl-4,6-dipiperidino-s-triazine The compound is obtained by following the same process as in Example 1. Recrystallization from petroleum ether yields 1.2 g. of the compound, M.P. 81-83" C.
  • the compound is obtained by following the same process as in Example 8. Recrystallization from ethanol yields 10.0 g. of the compound, M.P. 231-233 C.
  • Example 10 -2-methyl-4,6-di-n-hexylamino-s-triazine The compound is obtained by following the same process as in Example 2. Recrystallization from ethyl acetate yields 3.0 g. of the compound, M.P. 154-155 C.
  • Example 11-2-n-butyl-4,6-di-n-hexylamino-s-triazine The compound is obtained by following the same process as in Example 2. Recrystallization from ethyl acetate yields 1.0 g. of the compound, M.P. 97-98 C.
  • Example 12 -2-amino-4-cyclohexylamino-6- piperidino-s-triazine Piperidine (5.1 g.) is added, with stirring, to a mixture of 2-amino-4-cyclohexylamino-6-chloro-s-triazine (6.8 g.) in water (150 ml.). The mixture is slowly heated to reflux and the refluxing temperature is maintained for 2.5 hours. After cooling, the reaction 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 which is treated with ethanol-water to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from 60% ethanol to give the compound as colorless needles, M.P. 123-127 C. Yield is 3.0 g.
  • Example 132-amino-4-cyclohexy1amino-6-(Z-ketd piperazine-4-yl)-s-triazine A solution of 2-ketopiperazine (5.4 g.) in water (50 ml.) is added, with stirring, to a mixture of 2-amino-4- cyclohexylamino-6-chloro-s-triazine (6.1 g.) in water (150 ml.). The mixture is slowly heated to reflux and the refluxing temperature is maintained for 3 hours.
  • Example 14.2-ethyl-4,6-diphenethylamino-s-triazine The compound is obtained by following the same process as in Example 2, except that 2-ethyl-4,6-dichloro-striazine (3.6 g.) is employed instead of 2-n-butyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 4.4 g. of the compound, M.P. 147-148 C.
  • Example 15.2-n-propyl-4,6-diphenethylaminos-triazine The compound is obtained by following the same process as in Example 2, except that 2-n-propyl-4,6-dichloros-triazine (3.8 g.) is employed instead of 2-n-butyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 5.9 g. of the compound, M.P. 96-97 C.
  • Example 16.2-isopropyl-4,6-diphenethylamino-striazine I The compound is obtained by following the same process as in Example 2, except that 2-isopropyl-4,6-dichloros-triazine (3.8 g.) is employed instead of 2-n-butyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 5.0 g. of the compound, M.P. 90-91 C.
  • Example 17 -2-ethyl-4,6-dicyclohexylamino-s-triazine
  • the compound is obtained by following the same process as in Example 3, except that 2-ethyl-4,6-dichloro-striazine (3.6 g.) is employed instead of 2-methyl-4,6-dichloro-s-triazine. Recrystallization from acetonitrile yields 4.5 g. of the compound, M.P. 179 C.
  • Example 18.2-n-propyl-4,6-dicyclohexylaminos-triazine The compound is obtained by following the same process as in Example 3, except that 2-n-propyl-4,6-dichloros-triazine (3.8 g.) is employed instead of 2-methyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 4.3 g. of the compound, M.P. 145146 C.
  • Example 19 -2-isopropyl-4,6-dicyclohexylaminos-triazine
  • the compound is obtained by following the same process as in Example 3, except that 2-isopropyl-4,6-dichloros-triazine (3.8 g.) is employed instead of 2-methyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 5.5 g. of compound, M.P. 149-150 C.
  • Example 20 2-n-hexyl-4,6-dicyclohexylamino-s-triazine
  • the compound is obtained by following the same process as in Example 3, except that 2-n-hexyl-4,6-dichloro-striazine (4.7 g.) is employed instead of 2-methyl-4,6-dichloro-s-triazine. Recrystallization from acetonitrile yields 6.3 g. of the compound, M.P. 114 C.
  • Example 22 2-amino-4-phenethylamino-6-n-propyl-striazine
  • the compound is obtained by following the same process as in Example 21, except that ethyl butylate (15.0 g.) is employed instead of ethyl propionate. Recrystallization from isopropanol yields 12.2 g. of the compound, M.P. 8991 C.
  • Example 23 2-amino-4-phenethylamino-6-isopropyl-striazine
  • the compound is obtained by following the same process as in Example 21, except that ethyl isobutylate (15.0 g.) is employed instead of ethyl propionate. Recrystallization from acetonitrile yields 12.2 g. of the compound, M.P. -81 C.
  • Example 24 2-amino-4-phenethylamino-6-n-butyl-striazine
  • the compound is obtained by following the same process as in Example 21, except that ethyl valerate (17.0 g.) is employed instead of ethyl propionate. Recrystallization from isopropanol yields 13.4 g. of the compound, M.P. 93-95 C.
  • Example 25 -2-amino-4-phenethylamino 6-isobutyl-striazine
  • the compound is obtained by following the same process as in Example 21. Recrystallization from isopropanol yields 11.3 g. of the compound, M.P. 109-1105 C.
  • Example 26 2-'amino-4cyclohexylamino-G-methylamino-s-triazine 40% methylamine (4.7 g.) is added, with stirring, to a mixture of 2-amino-4-cyclohexylamino-6-chloro-s-triazine (6.8 g.) in water (150 ml.). The mixture is slowly heated to reflux and the refluxing temperature is maintained for 2 hours. After cooling, the product is collected by filtration and recrystallized from acetonitrile to give the com pound as white crystals, M.P. 189-190 C. Yield is 4.9 g.
  • Example 27 -2-amino-4-1cyclohexylamino-6-ethy1- amino-s-triazine maleate 70% ethylamine (3.9 g.) is added, with stirring, to a mixture of 2 amino 4 cyclohexylamino 6 chloro-striazine (6.8 g.) in water (150 ml.). The mixture is slowly heated to reflux and the refluxing temperature is maintained for 2 hours. After cooling, the reaction mixture is extracted with ethyl acetate and the ethyl acetate solution is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a syrup.
  • Example 28 2-amino-4-cyclohexylamino-6-n-propylamino-s-triazine maleate
  • the compound is obtained by following the same process as in Example 27. Recrystallization from acetonitrile yields 4.5 g. of the compound, M.P. 169-170 C.
  • Example 29 -2-amino-4-cyclohexylamino-6-n-butylamino-s-triazine maleate
  • the -compound is obtained by following the same process as in Example 27. Recrystallization from methanol yields 3.7 g. of the compound, M.P. 156158 C.
  • Example 30 2-amino-4-cyclohexylamino-6-dimethy1- amino-s-triazine maleate
  • the compound is obtained by following the same process as in Example 13. Recrystallization from lacetonitrile yields 5.2 g. of the compound, M.P. 134-136" C.
  • Example 31 -2-amino-4-cyclohexylamino-6-diethylamino-s-triazine maleate
  • the compound is obtained by following the same process as in Example 27. Recrystallization from acetonitrile yields g. of the compound, M.P. 167169 C.
  • Example 32 -2-amino-4-cyclohexylamino-6-di-npropylamino-s-triazine maleate
  • the compound is obtained by following the same process as in Example 27. Recrystallization from acetonitrile yields 5.0 g. of the compound, M.P. 132 C.
  • Example 33 -2-amino-4-cyclohexylamino-6-di-nbutylamino-s-triazine maleate References Cited UNITED STATES PATENTS 2,909,420 10/1959 Gysin et al. 260-249.9 X 2,909,421 10/1959 Gysin et al. 260-249.6 X

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Abstract

NOVEL S-TRIAZINE DERIVATIVES HAVING ANTI-INFLAMMATORY AND ANTI-ATHEROSCLEROTIC ACTIVITY AND OF THE FORMULA

2-R2,4-R1,6-R3-S-TRIAZINE

WHEREIN R1 STANDS FOR PHENETHYLAMINO, ARALKYLAMINO, PYRROLIDINO, PIPERIDINO, 2-KETOPIPERAZINE-4-YL, CYCLOHEXYLAMINO OR STRAIGHT OR BRANCHED HEXYLAMINO; R2 STANDS FOR AMINO, ARALKYLAMINO, PYRROLIDINO, PIPERIDINO 2-KETOPIPERAZINE-4-YL, CYCLOHEXYLAMINO OR STRAIGHT OR BRANCHED HEXYLAMINO; AND R3 STANDS FOR STRAIGHT OR BRANCHED ALKYL OF FROM 1-6 CARBON ATOMS, PYRROLIDINO, PIPERIDINO, 2-KETOPIPERAZINE4-YL OR NR4R5 IN WHICH R4 IS HYDROGEN OR STRAIGHT OR BRANCHED ALKYL OF FROM 1-6 CARBON ATOMS AND R5 IS STRAIGHT OR BRANCHED ALKYL WITH FROM 1-6 CARBON ATOMS, WITH THE PROVISO THAT (A) WHEN R1 IS PHENETHYLAMINO, R2 IS AMINO AND R3 IS STRAIGHT OR BRANCHED ALKYL OF FROM 2-6 CARBON ATOMS; (B) WHEN R1 IS ARALKYLAMINO, PYRROLIDINO, PIPERIDINO OR 2-KETOPIPERAZINE-4-YL, R2 IS THE SAME OR ONE OF SAID GROUPS AND R3 IS STRAIGHT OR BRANCHED ALKYL OF FROM 1-6 CARBON ATOMS; (C) WHEN R1 IS CYCLOHEXYLAMINO OR STRAIGHT OR BRANCHED HEXYLAMINO, R2 IS THE SAME OR ONE OF SAID GROUPS AND R3 IS STRAIGHT OR BRANCHED ALKYL OF FROM 1-6 CARBON ATOMS; AND (D) WHEN R1 IS CYCLOHEXYLAMINO, R2 IS AMINO AND R3 IS PYRROLIDINO, PIPERIDINO, 2-KETOPIPERAZINE-4-YL OR NR4R5, WHEREIN R4 AND R5 HAVE THE ABOVE MEANING.

Description

United States Patent 3,758,471 TRIAZINE DERIVATIVES Tsutomu Irikura, Yasuo Abe, Kyuya Okamura, Kyoichi Higo, Akitoshi Maeda, and F umihiko Morinaga, Tokyo, Japan, assignors to Kyorin Seiyaku Kabushiki Kaisha No Drawing. Continuation of abandoned application Ser. No. 808,683, Mar. 19, 1971. This application June 15, 1971, Ser. No. 153,396
Claims priority, application Japan, Apr. 10, 1968, 43/23,906, 43/23,907; June 6, 1968, 43/318,831; June 28, 1968, 43/44,996
Int. Cl. C07d 55/20, 55/22 U.S. Cl. 260249.6 3 Claims ABSTRACT OF THE DISCLOSURE Novel s-triazine derivatives having anti-inflammatory and anti-atherosclerotic activity and of the formula R stands for phenethylamino, aral-kylamino, pyrrolidino, piperidino, 2-ketopiperazine-4-yl, cyclohexylamino or straight or branched hexylamino;
R stands for amino, aralkylamino, pyrrolidino, piperidino, 2-ketopiperazine-4-y1, cyclohexylamino or straight or branched hexylamino; and
R stands for straight or branched alkyl of from 1-6 carbon atoms, pyrrolidino, piperidino, Z-ketopiperazine- 4-yl or NR R in which R, is hydrogen or straight or branched alkyl of from 1-6 carbon atoms and R is straight or branched alkyl with from 1-6 carbon atoms, with the proviso that (a) when R is phenethylamino, R is amino and R is straight or branched alkyl of from 26 carbon atoms;
(b) when R is aralkylamino, pyrrolidino, piperidino or 2-ketopiperazine-4-yl, R is the same or one of said groups and R is straight or branched alkyl of from 1-6 carbon atoms;
(0) when R, is cyclohexylamino or straight or branched hexylamino, R is the same or one of said groups and R is straight or branched alkyl of from 1-6 carbon atoms; and
(d) when R is cyclohexylamino, R is amino and R is pyrrolidino, piperidino, 2-ketopiperazine-4-yl or NR R wherein R and R have the above meaning.
wherein CROSS-REFERENCE TO PRIOR APPLICATION This is a continuation application of Ser. No. 808,683, filed Mar. 19, 1969, now abandoned.
SUMMARY OF THE INVENTION The invention relates to s-triazine derivatives of the formula N F i k a wherem R stands for phenethylamino, aralkylamino, pyrrolidino, piperidino, 2-ketopiperazine-4-y1, cyclohexylamino or straight or branched hexylamino;
R stands for amino, aralkylamino, pyrrolidino, piperidino, 2-ketopiperazine-4-yl, cyclohexylamino or straight or branched hexylamino; and
R stands for straight or branched alkyl of from 1-6 carbon atoms, pyrrolidino, piperidino, Z-ketopiperazine- 4-yl or NR R in which R is hydrogen or straight or branched alkyl of from 1-6 carbon atoms and R is straight or branched alkyl with from 1-6 carbon atoms, with the proviso that (a) when R is phenethylarnino, R is amino and R is straight or branched alkyl of from 2-6 carbon atoms;
(b) when R is aralkylamino, pyrrolidino, piperidino or 2-ketopiperazine-4-yl, R is the same or one of said groups and R is straight or branched alkyl of from 1-6 carbon atoms;
(c) when R is cyclohexylamino or straight or branched hexylamino, R is the same or one of said groups and R is straight or branched alkyl of from 1-6 carbon atoms; and
(d) when R is cyclohexylamino, R is amino and R is pyrrolidino, piperidino, 2-ketopiperazine-4-y1 or NR R wherein R and R have the above meaning.
The invention also embraces the acid addition salts of the compounds with organic or inorganic acids such as hydrochloric acid, maleic acid, tartaric acid, citric acid and lactic acid.
Activation of the reticuloendothelial system (RES) in mice is remarkably suppressed by preadministration of a compound having anti-inflammatory and auti-atherosclerotic activity. Therefore it is found that there is a strong correlation between RES and the compound and this correlation is used as a screening means to determine the utility of the present inventive compounds. The results of the physiological activities of the present inventive compounds by the above method are shown in Table I.
TABLE I Compound of Mean compound Example No.: activity 1 2 129.9 3 211.5
The correlation between the results of the above screening and the anti-inflammatory and anti-atherosclerotic activity is explained in a copending application.
The s-triazine derivatives of the present invention exhibit anti-inflammatory and/ or anti-atherosclerotic activity. Further, various cortison-like or oortison-inhibitory activities have also been observed in the novel s-tri azine derivatives. The inventive compounds are therefore not only pharmacologically useful as anti-atherosiclerotic agents, but they are also anti-inflammatory agents which may replace steroidal anti-inflammatory agents.
The compounds of the present invention can be prepared by two processes which are represented by the following schemes:
Process A:
wherein X is amino or alkyl and Y and Z are the same or different amino radicals.
Process B:
RCOOR b/ N W$|1NHC-NH, L I
wherein Wis phenethylamino, R is straight or branched alkyl of from 26 carbon atoms and R is lower alkyl.
Example 1.2-methyl-4,6-diphenethylamino-s-triazine A solution of phenethylamine (4.8 g.) in chloroform (20 ml.) is added in dropwise manner and under cooling to a solution of 2-methyl-4,6-dichloro-s-triazine (3.2 g.) in chloroform (80 ml.). A solution of potassium icarbonate (8.2 g.) in water (10 m1.) is also added to the reaction mixture. After completing the addition, stirring is continued for some time. The chloroform solution is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a crystalline precipitate. The precipitate is recrystallized from ethanol to yield 2-methyl-4,6-diphenethylamino-s-triazine as colorless crystals, M.P. 213-214 C. The yield is 1.0 g.
Analysis.--Calcd. for C H N (percent): C, 72.04; H, 6.95; N, 21.01. Found (percent): C, 72.18; H, 7.08; N, 21.12.
Example 2.-2-n-butyl-4,G-diphenethylamino-s-triazine Phenethylamine (9.7 g.) is added, with stirring, to a mixture of 2-n-butyl-4,6-dichloro-s-triazine (4.2 g.) in water (100 ml.). The mixture is slowly heated to reflux, and the refluxing temperature is maintained for 2 hours. After cooling, the product is collected by filtration and recrystallized from acetonitrile to give 2-n-butyl-4,6-diphenethylamino-s-triazine as colorless needles, M.P. 66- 67" C. The yield is 4.0 g.
Analysis.-Calcd. for C H N (percent): C, 73.56; H, 7.78; N, 18.65. Found (percent): C, 73.00; H, 7.80; N, 18.69.
Example 3.-2-methyl-4,6-dicyclohexylamino-s-triazine Cyclohexylamine (8.0 g.) is added, with stirring, to a mixture of 2-methyl-4,6-dichloro-s-triazine (3.2 g.) in Water (100 ml.). The mixture is slowly heated to reflux, and the refluxing temperature is maintained for 2 hours. After cooling, the product is collected by filtration and recrystallized from ethyl acetate to give 2-methyl-4,6-dicyclohexylamino-s-triazine as colorless needles, M.P. 187- 189 C. The yield is 3.7 g.
4 Analysis.Calcd. for C H N (percent): C, 66.39; H, 9.40; N, 24.21. Found (percent): C, 66.23; H, 9.29; N, 23.05.
Example 4.2-n-butyl-4,6-dicyclohexylamino-s-triazine The compound is obtained by following the same process as in Example 3, except that 2-n-butyl-4,6-dichloro-striazine (4.2 g.) is employed instead of 2-methyl-4,6-dichloro-s-triazine. Recrystallization from n-hexane yields 3.0 g. of the compound, M.P. l36137 C.
Analysis.Calcd. for C H N (percent): C, 68.84; H, 10.03; N, 21.13. Found (percent): C, 69.35; H, 10.17; N, 21.14.
Example 5.2-methyl-4,6-dipyrrolidino-s-triazine The compound is obtained by following the same process as in Example 1. Recrystallization from petroleum ether yields 1.0 g. of the compound, M.P. 83-85 C.
Analysis.-Calcd. for C H N (percent): C, 61.77; H, 8.21; N, 30.02. Found (percent): C, 61.53; H, 8.11; N, 30.35.
Example 6.2-methyl-4,6-di(2-ketopiperazine- 4-yl)-s-triazine The compound is obtained by following the same process as in Example 2. Recrystallization from ethanol yields 1.0 g. of the compound, M.P. 303 C. (dec.).
Analysis.Calcd. for C H N 0 (percent): C, 49.47; H, 5.88; N, 33.66. Found (percent): C, 49.18; H, 5.87; N, 34.34.
Example 7.2-methyl-4,6-dipiperidino-s-triazine The compound is obtained by following the same process as in Example 1. Recrystallization from petroleum ether yields 1.2 g. of the compound, M.P. 81-83" C.
Analysis.-Calcd. for C H N (percent): 0, 64.33; H, 8.87; N, 26.80. Found (percent): C, 64.09; H, 8.70; N, 27.19.
Example 8.2-methyl-4-pyrrolidino-6-phenethylamino s-triazine Example 9.-2-methyl-4-phenethylamino-6-(2-ketopiperazine-4-yl)-s-triazine The compound is obtained by following the same process as in Example 8. Recrystallization from ethanol yields 10.0 g. of the compound, M.P. 231-233 C.
Analysis.-Calcd. for C H N O (percent): C, 61.52; H, 6.45; N, 26.91. Found (percent): C, 61.14; H, 6.38; N, 26.32.
Example 10.-2-methyl-4,6-di-n-hexylamino-s-triazine The compound is obtained by following the same process as in Example 2. Recrystallization from ethyl acetate yields 3.0 g. of the compound, M.P. 154-155 C.
Analysis.-Calcd. for C H N (percent): C, 65.48; H, 10.65; N, 23.87. Found (percent): C, 65.61; H, 10.60; N, 23.84.
Example 11.-2-n-butyl-4,6-di-n-hexylamino-s-triazine The compound is obtained by following the same process as in Example 2. Recrystallization from ethyl acetate yields 1.0 g. of the compound, M.P. 97-98 C.
Analysis.-Calcd. for C H N (percent): C, 68.01; H, 11.12; N, 20.87. Found (percent): C, 67.90; H, 11.03; N, 20.76.
Example 12.-2-amino-4-cyclohexylamino-6- piperidino-s-triazine Piperidine (5.1 g.) is added, with stirring, to a mixture of 2-amino-4-cyclohexylamino-6-chloro-s-triazine (6.8 g.) in water (150 ml.). The mixture is slowly heated to reflux and the refluxing temperature is maintained for 2.5 hours. After cooling, the reaction 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 which is treated with ethanol-water to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from 60% ethanol to give the compound as colorless needles, M.P. 123-127 C. Yield is 3.0 g.
Analysis.-Calcd. for C H N (percent): C, 60.84; H, 8.75; N, 30.41. Found (percent): C, 60.31; H, 8.64; N, 30.48.
I Example 13.2-amino-4-cyclohexy1amino-6-(Z-ketd piperazine-4-yl)-s-triazine A solution of 2-ketopiperazine (5.4 g.) in water (50 ml.) is added, with stirring, to a mixture of 2-amino-4- cyclohexylamino-6-chloro-s-triazine (6.1 g.) in water (150 ml.). The mixture is slowly heated to reflux and the refluxing temperature is maintained for 3 hours. After cooling, the product is collected by filtration and recrystallized from ethanol to give 2-amino-4-cyclohexylamino-6-(2- ketopiperazine-4-yl)-s-triazine as colorless crystals, M.P. 266-269 C. Yield is 2.3 g.
Analysis.Calcd. for C13H21N70 (percent): C, 53.59; H, 7.27; N, 33.66. Found (percent): C, 53.80; H, 7.37; N, 34.02.
Example 14.2-ethyl-4,6-diphenethylamino-s-triazine The compound is obtained by following the same process as in Example 2, except that 2-ethyl-4,6-dichloro-striazine (3.6 g.) is employed instead of 2-n-butyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 4.4 g. of the compound, M.P. 147-148 C.
Analysis.Calcd. for C H N (percent): C, 72.59; H, 7.25; N, 20.16. Found (percent): C, 72.45; H, 7.11; N, 20.26.
Example 15.2-n-propyl-4,6-diphenethylaminos-triazine The compound is obtained by following the same process as in Example 2, except that 2-n-propyl-4,6-dichloros-triazine (3.8 g.) is employed instead of 2-n-butyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 5.9 g. of the compound, M.P. 96-97 C.
Analysis.Calcd. for C H N (percent): C, 73.09; H, 7.53; N, 19.38. Found (percent): C, 73.08; H, 7.35; N, 19.23.
Example 16.2-isopropyl-4,6-diphenethylamino-striazine I The compound is obtained by following the same process as in Example 2, except that 2-isopropyl-4,6-dichloros-triazine (3.8 g.) is employed instead of 2-n-butyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 5.0 g. of the compound, M.P. 90-91 C.
Analysis.-Calcd. for C22H2'1N5 (percent): C, 73.09; H, 7.53; N, 19.38. Found (percent): C, 72.98; H, 7.59; N, 19.04.
Example 17.-2-ethyl-4,6-dicyclohexylamino-s-triazine The compound is obtained by following the same process as in Example 3, except that 2-ethyl-4,6-dichloro-striazine (3.6 g.) is employed instead of 2-methyl-4,6-dichloro-s-triazine. Recrystallization from acetonitrile yields 4.5 g. of the compound, M.P. 179 C.
6 Analysis.-Calcd. for C H N (percent): C, 67.29; H, 9.63; N, 23.08. Found (percent): C, 67.27; H, 9.60; N, 23.17.
Example 18.2-n-propyl-4,6-dicyclohexylaminos-triazine The compound is obtained by following the same process as in Example 3, except that 2-n-propyl-4,6-dichloros-triazine (3.8 g.) is employed instead of 2-methyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 4.3 g. of the compound, M.P. 145146 C.
Analysis.-Calcd. for C H N (percent): C, 68.10; H, 9.84; N, 22.06. Found (percent): C, 67.85; H, 9.73; N, 22.06.
Example 19.-2-isopropyl-4,6-dicyclohexylaminos-triazine The compound is obtained by following the same process as in Example 3, except that 2-isopropyl-4,6-dichloros-triazine (3.8 g.) is employed instead of 2-methyl-4,6- dichloro-s-triazine. Recrystallization from acetonitrile yields 5.5 g. of compound, M.P. 149-150 C.
Analysis.--Calcd. for C H N (percent): C, 68.10; 113, 9.84; N, 22.06. Found (percent): C, 68.07; H, 9.85;
Example 20.2-n-hexyl-4,6-dicyclohexylamino-s-triazine The compound is obtained by following the same process as in Example 3, except that 2-n-hexyl-4,6-dichloro-striazine (4.7 g.) is employed instead of 2-methyl-4,6-dichloro-s-triazine. Recrystallization from acetonitrile yields 6.3 g. of the compound, M.P. 114 C.
Analysis.Calcd. for C H N (percent): C, 70.15; H, 10.37; N, 19.48. Found (percent): C, 70.18; H, 10.32; N, 19.60.
Example 21.-2-amino-4-phenethylamino-6-ethyl-striazine Phenethylbiguanide hydrochloride (24.1 g.) is added to a solution of sodium (2.3 g.) methanol and sodium chloride formed is removed by filtration. To the filtrate is added, with stirring, ethyl propionate (10.2 g.) under cooling (40 C.). The mixture is stirred at room temperature for 4 hours and treated with water (800 ml.). On standing several days, the product is collected by filtration and recrystallized from isopropylalcohol to give 2-amino-4-phenethyl-6-ethyl-s-triazine as colorless prismatic crystals, M.P. 140.5-142 C. Yield is 11.4 g.
Analysis.Calcd. for C H N (percent): C, 64.17; H, 7.04; N, 28.79. Found (percent): C, 64.07; H, 7.12; N, 28.59.
Example 22.2-amino-4-phenethylamino-6-n-propyl-striazine The compound is obtained by following the same process as in Example 21, except that ethyl butylate (15.0 g.) is employed instead of ethyl propionate. Recrystallization from isopropanol yields 12.2 g. of the compound, M.P. 8991 C.
Analysis.Calcd. for C H N (percent): C, 65.34; H, 7.44; N, 27.22. Found (percent): C, 64.94; H, 7.77; N, 2709.
Example 23 .2-amino-4-phenethylamino-6-isopropyl-striazine The compound is obtained by following the same process as in Example 21, except that ethyl isobutylate (15.0 g.) is employed instead of ethyl propionate. Recrystallization from acetonitrile yields 12.2 g. of the compound, M.P. -81 C.
Analysis.Calcd. for C H N (percent): C, 65.34; H, 7.44; N, 27.22. Found (percent): C, 65.12; H, 7.36; N, 27.57.
Example 24.2-amino-4-phenethylamino-6-n-butyl-striazine The compound is obtained by following the same process as in Example 21, except that ethyl valerate (17.0 g.) is employed instead of ethyl propionate. Recrystallization from isopropanol yields 13.4 g. of the compound, M.P. 93-95 C.
Analysis.Calcd. for C H N (percent): C, 66.39; H, 7.80; N, 25.18. Found (percent): C, 65.70; H, 7.68; N, 25.90.
Example 25.-2-amino-4-phenethylamino 6-isobutyl-striazine The compound is obtained by following the same process as in Example 21. Recrystallization from isopropanol yields 11.3 g. of the compound, M.P. 109-1105 C.
Analysis.Calcd. for C H N (percent): C, 66.39; H, 7.80; N, 25.81. Found (percent): C, 66.19; H, 7.86; N, 26.06.
Example 26.2-'amino-4cyclohexylamino-G-methylamino-s-triazine 40% methylamine (4.7 g.) is added, with stirring, to a mixture of 2-amino-4-cyclohexylamino-6-chloro-s-triazine (6.8 g.) in water (150 ml.). The mixture is slowly heated to reflux and the refluxing temperature is maintained for 2 hours. After cooling, the product is collected by filtration and recrystallized from acetonitrile to give the com pound as white crystals, M.P. 189-190 C. Yield is 4.9 g.
Analysis.Calcd. for C H N (percent): C, 54.03; H, 8.16; N, 37.81. Found (percent): C, 54.12; H, 8.25; N, 37.94.
Example 27.-2-amino-4-1cyclohexylamino-6-ethy1- amino-s-triazine maleate 70% ethylamine (3.9 g.) is added, with stirring, to a mixture of 2 amino 4 cyclohexylamino 6 chloro-striazine (6.8 g.) in water (150 ml.). The mixture is slowly heated to reflux and the refluxing temperature is maintained for 2 hours. After cooling, the reaction mixture is extracted with ethyl acetate and the ethyl acetate solution is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a syrup. The syrup is dissolved in methanol (20 ml.), added to a solution of maleic acid (2.3 g.) in methanol (10 ml.) and the mixture is refluxed for 1 hour to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from ethanol to give the compound as white crystal-powder, M.P. 160161 C. Yield is 3.6 g.
Analysis.Calcd. for C H N O (percent): C, 51.12; H, 6.87; N, 23.85. Found (percent): C, 51.20; H, 6.86; N, 23.63.
Example 28.2-amino-4-cyclohexylamino-6-n-propylamino-s-triazine maleate The compound is obtained by following the same process as in Example 27. Recrystallization from acetonitrile yields 4.5 g. of the compound, M.P. 169-170 C.
Analysis.Calcd. for C H N O (percent): C, 52.44; H, 7.15; N, 22.94. Found (percent): C, 52.57; H, 7.29; N, 22.96.
Example 29.-2-amino-4-cyclohexylamino-6-n-butylamino-s-triazine maleate The -compound is obtained by following the same process as in Example 27. Recrystallization from methanol yields 3.7 g. of the compound, M.P. 156158 C.
Analysis.Calcd. for C H N O (percent): C, 53.66; H, 7.42; N, 22.09. 'Found (percent): C, 53.62; H, 7.55; N, 22.16.
Example 30.2-amino-4-cyclohexylamino-6-dimethy1- amino-s-triazine maleate The compound is obtained by following the same process as in Example 13. Recrystallization from lacetonitrile yields 5.2 g. of the compound, M.P. 134-136" C.
Analysis.Calcd. for C H N (percent): C, 55.90; H, 8.53; N, 35.57. Found (percent): C, 55.97; H, 8.69; N, 35.27.
Example 31.-2-amino-4-cyclohexylamino-6-diethylamino-s-triazine maleate The compound is obtained by following the same process as in Example 27. Recrystallization from acetonitrile yields g. of the compound, M.P. 167169 C.
Analysis.Calcd. for C17H28N6O4 (percent): C, 53.66; H, 7.42; N, 22.09. Found (percent): C, 53.66; H, 7.26; N, 22.06.
Example 32.-2-amino-4-cyclohexylamino-6-di-npropylamino-s-triazine maleate The compound is obtained by following the same process as in Example 27. Recrystallization from acetonitrile yields 5.0 g. of the compound, M.P. 132 C.
AnaIysis.--Calcd. for C H N O (percent): C, 55.86; H, 7.90; N, 20.58. Found (percent): C, 55.50; H, 7.96; N, 20.69.
Example 33.-2-amino-4-cyclohexylamino-6-di-nbutylamino-s-triazine maleate References Cited UNITED STATES PATENTS 2,909,420 10/1959 Gysin et al. 260-249.9 X 2,909,421 10/1959 Gysin et al. 260-249.6 X
JOHN M. FORD, Primary Examiner US. Cl. X.R.
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US20040077648A1 (en) * 2001-09-21 2004-04-22 Timmer Richard T. Methods and compositions of novel triazine compounds
US20040209882A1 (en) * 2001-09-21 2004-10-21 Timmer Richard T. Methods and compositions of novel triazine compounds
US20040209880A1 (en) * 2001-09-21 2004-10-21 Timmer Richard T. Methods and compositions of novel triazine compounds
US20040224950A1 (en) * 2001-09-21 2004-11-11 Timmer Richard T. Methods and compositions of novel triazine compounds
US20050113341A1 (en) * 2001-09-21 2005-05-26 Timmer Richard T. Medical devices employing triazine compounds and compositions thereof
US20050227983A1 (en) * 2004-03-24 2005-10-13 Timmer Richard T Triazine compounds and their analogs, compositions, and methods

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WO1997008156A1 (en) * 1995-08-24 1997-03-06 Hoechst Schering Agrevo Gmbh 2,4- diamino-1,3,5-triazines, process for the production thereof, and the use thereof as herbicides and plant growth regulators
US6239071B1 (en) 1995-08-24 2001-05-29 Hoecht Schering Agrevo Gmbh 2,4-diamino-1,3,5-triazines, processes for their preparation and their use as herbicides and plant growth regulators
US20070004729A1 (en) * 2001-09-21 2007-01-04 Timmer Richard T Methods and compositions of novel triazine compounds
US20070122444A1 (en) * 2001-09-21 2007-05-31 Timmer Richard T Medical devices employing triazine compounds and compositions thereof
US20040209880A1 (en) * 2001-09-21 2004-10-21 Timmer Richard T. Methods and compositions of novel triazine compounds
US20040224950A1 (en) * 2001-09-21 2004-11-11 Timmer Richard T. Methods and compositions of novel triazine compounds
US20050113341A1 (en) * 2001-09-21 2005-05-26 Timmer Richard T. Medical devices employing triazine compounds and compositions thereof
US20050124619A1 (en) * 2001-09-21 2005-06-09 Timmer Richard T. Medical devices employing triazine compounds and compositions thereof
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