US3759911A - Triazine derivatives - Google Patents

Triazine derivatives Download PDF

Info

Publication number
US3759911A
US3759911A US00153395A US3759911DA US3759911A US 3759911 A US3759911 A US 3759911A US 00153395 A US00153395 A US 00153395A US 3759911D A US3759911D A US 3759911DA US 3759911 A US3759911 A US 3759911A
Authority
US
United States
Prior art keywords
triazine
mixture
amino
phenethylamino
methanol
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 - Lifetime
Application number
US00153395A
Other languages
English (en)
Inventor
T Irikura
F Morinaga
K Higo
A Maeda
Y Abe
K Okamura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kyorin Pharmaceutical Co Ltd
Original Assignee
Kyorin Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kyorin Pharmaceutical Co Ltd filed Critical Kyorin Pharmaceutical Co Ltd
Application granted granted Critical
Publication of US3759911A publication Critical patent/US3759911A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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

  • the new compounds exhibit anti-inflammatory and antiatherosclerotic activity.
  • 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.
  • inventive compounds can be prepared according to the following reaction scheme:
  • Each value is the average value obtained in testing 5 mice.
  • 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.
  • inventive compounds were administered, 300- mg./ kg., orally one hour before injection of typhoid-paratyphoid-vaccine.
  • 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.
  • 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.
  • Example 1 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.
  • a different experimental group of rabbits received a cholesterol diet for 80 days and then was put on normal diet.
  • 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.
  • Example 1 The anti-inflammatory activity of the Example 1 compound was demonstrated by the following:
  • Example 1 compound 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.
  • Example 1 compound 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.
  • inventive triazine derivatives 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Mechanical Engineering (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US00153395A 1968-04-10 1971-06-15 Triazine derivatives Expired - Lifetime US3759911A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2390768 1968-04-10
JP2390668 1968-04-10
JP2390568 1968-04-10
JP3883168 1968-06-06
JP4499668 1968-06-28
US15339571A 1971-06-15 1971-06-15

Publications (1)

Publication Number Publication Date
US3759911A true US3759911A (en) 1973-09-18

Family

ID=27549132

Family Applications (2)

Application Number Title Priority Date Filing Date
US00153395A Expired - Lifetime US3759911A (en) 1968-04-10 1971-06-15 Triazine derivatives
US00153396A Expired - Lifetime US3758471A (en) 1968-04-10 1971-06-15 Triazine derivatives

Family Applications After (1)

Application Number Title Priority Date Filing Date
US00153396A Expired - Lifetime US3758471A (en) 1968-04-10 1971-06-15 Triazine derivatives

Country Status (5)

Country Link
US (2) US3759911A (fi)
BE (2) BE726948A (fi)
DE (2) DE1907589C3 (fi)
FR (2) FR2005901A1 (fi)
GB (2) GB1250971A (fi)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5332737A (en) * 1989-12-05 1994-07-26 Imperial Chemical Industries Plc Amino-1,3,5-triazines and their anhydrobase derivatives as agents for cardiovascular system
US20110237587A1 (en) * 2007-08-31 2011-09-29 Hanall Pharmaceutical Company, Ltd 1,3,5-Triazine-2,4,6-Triamine Compound or Pharmaceutical Acceptable Salt Thereof, and Pharmaceutical Composition Comprising the Same
CN108191774A (zh) * 2018-01-31 2018-06-22 中国药科大学 一类杂环化合物、其制备方法和用途

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19531084A1 (de) 1995-08-24 1997-02-27 Hoechst Schering Agrevo Gmbh 2,4-Diamino-1,3,5-triazine, Verfahren zu deren Herstellung und deren Verwendung als Herbizide und Pflanzenwachstumsregulatoren
US7112587B2 (en) * 2001-09-21 2006-09-26 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7132423B2 (en) * 2001-09-21 2006-11-07 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7173032B2 (en) * 2001-09-21 2007-02-06 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7163943B2 (en) * 2001-09-21 2007-01-16 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7169785B2 (en) * 2001-09-21 2007-01-30 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7335770B2 (en) * 2004-03-24 2008-02-26 Reddy U5 Therapeutics, Inc. Triazine compounds and their analogs, compositions, and methods

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5332737A (en) * 1989-12-05 1994-07-26 Imperial Chemical Industries Plc Amino-1,3,5-triazines and their anhydrobase derivatives as agents for cardiovascular system
US5574037A (en) * 1989-12-05 1996-11-12 Imperial Chemical Industries Plc Amino 1,3,5-triazine derivatives as agents for cardiovascular system
US20110237587A1 (en) * 2007-08-31 2011-09-29 Hanall Pharmaceutical Company, Ltd 1,3,5-Triazine-2,4,6-Triamine Compound or Pharmaceutical Acceptable Salt Thereof, and Pharmaceutical Composition Comprising the Same
US8722674B2 (en) * 2007-08-31 2014-05-13 Hanall Biopharma Co., Ltd. 1,3,5-triazine-2,4,6-triamine compound or pharmaceutical acceptable salt thereof, and pharmaceutical composition comprising the same
CN108191774A (zh) * 2018-01-31 2018-06-22 中国药科大学 一类杂环化合物、其制备方法和用途
CN108191774B (zh) * 2018-01-31 2022-05-24 中国药科大学 一类杂环化合物、其制备方法和用途

Also Published As

Publication number Publication date
DE1907589C3 (de) 1974-06-27
GB1252870A (fi) 1971-11-10
DE1913154A1 (de) 1969-12-04
FR2005901A1 (fi) 1969-12-19
GB1250971A (fi) 1971-10-27
US3758471A (en) 1973-09-11
FR2005902A1 (fi) 1969-12-19
DE1907589A1 (de) 1969-10-30
BE726947A (fi) 1969-07-01
DE1913154C3 (de) 1974-04-11
BE726948A (fi) 1969-07-01
DE1907589B2 (de) 1973-11-29
DE1913154B2 (de) 1973-08-16

Similar Documents

Publication Publication Date Title
DE69120100T2 (de) Annelierte Thiophen-Derivate, ihre Herstellung und Verwendung
DE69023928T2 (de) DIAMINVERBINDUNGEN UND ARZNEIMITTEL GEGEN CEREBRALE STöRUNGEN DIE DIESE ENTHALTEN.
DE3441975C2 (fi)
US3759911A (en) Triazine derivatives
DE19962300A1 (de) Substituierte N-Benzyl-Indol-3-yl-glyoxylsäure-Derivate mit Antitumorwirkung
DE3780259T2 (de) Imidazolidinon-verbindungen, verfahren zu deren herstellung, zusammensetzungen die diese verbindungen enthalten und deren anwendung fuer die fabrikation von arzneimitteln mit einem therapeutischen wert.
DE69428620T2 (de) Benzoxazule Derivate und ihre Anwendung als Serotonin 5HT3 Rezeptor Antagonisten
DE69329385T2 (de) Thiazolin-derivate
DE2461802A1 (de) Pyrazinderivate
DE2128375C3 (de) Basische substituierte Alkylidenamino-oxyalkyl-carbonsäureester, deren Säureadditionssalze, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Präparate
US3694450A (en) 2-substituted-4,5,6,7-tetrahydrobenzothiazole-4-carboxylic acids and their alkyl esters
DE2456098C3 (de) Xanthen- und Thioxanthen-Derivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
DE3642497A1 (de) Substituierte aminopropionsaeureamide, verfahren zu ihrer herstellung, diese enthaltende mittel und ihre verwendung sowie die bei der herstellung anfallenden neuen zwischenprodukte
DE3853958T2 (de) Substituierte Pyridin-Verbindungen, ihre Herstellung und sie enthaltende pharmazeutische Zusammensetzungen.
US4220645A (en) Chromone derivatives
DE69426372T2 (de) Neue 1-Phenylmethyl-benzimidazol-piperazinderivate
US3803161A (en) 2-substituted-4,5,6,7-tetrahydrobenzothiazole-4-carboxylic acids and their alkyl esters
DE1944759B2 (de) 3-Indolylacetamide, ihre Salze und Verfahren zu ihrer Herstellung
US3787433A (en) 2-substituted-4,5,6,7-tetrahydrobenzothiazole-4-carboxylic acids and their alkyl esters
US3859280A (en) 2-substituted-4,5,6-tetrahydrobenzothiazole-4-carboxylic acids and their alkyl esters
US3234219A (en) 5-nitro-furyl-(2)-methylidene hydrazides
DE69027300T2 (de) 1,2-dihydro-2-oxoquinoxalinderivate, deren herstellung und verwendung in der therapie
DE2503436A1 (de) 2-substituierte 4,5-diphenylthiazole, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
US3350407A (en) Sulfur containing pyrazole derivatives
CH461489A (de) Verfahren zur Herstellung von neuen Oxazolderivaten