US3536709A - 2 - trichloromethyl - 4 - morpholino-6-(succinyloxy alkyl)amino - s - triazines and lower alkyl esters thereof - Google Patents

2 - trichloromethyl - 4 - morpholino-6-(succinyloxy alkyl)amino - s - triazines and lower alkyl esters thereof Download PDF

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Publication number
US3536709A
US3536709A US640349A US3536709DA US3536709A US 3536709 A US3536709 A US 3536709A US 640349 A US640349 A US 640349A US 3536709D A US3536709D A US 3536709DA US 3536709 A US3536709 A US 3536709A
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Prior art keywords
morpholino
trichloromethyl
triazine
amino
alkyl
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US640349A
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English (en)
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Werner Heimberger
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Evonik Operations GmbH
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Degussa GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the compounds are useful as analgesics and as antiinfiammatory agents.
  • the invention relates to novel dicarboxylic acid derivatives of 2,4,6 substituted s-triazines [which are useful as antiinflammatory agents and particularly as analgesics.
  • the invention concerns novel dicarboxylic acid derivatives of s-triazine of the formula in which R and R may be the same or diiferent and signifying alkoxyor alkylthio of 1 to 4 carbon atoms, a straight or branched monoalkylamino or monoalkanolamino group of 1 to 4 carbon atoms, CCl CHCl 3,536,709 Patented Oct. 27, 1970 'Ol, morpholino, piperazino or N-alkyl pipera/zino in which the alkyl is of 1 to 4 carbon atoms and R signifies as well as their alkyl esters wherein the alkyl is of 1 to 4 carbon atoms.
  • the compounds are useful as analgesics and as antiinflammatory agents.
  • novel compounds according to the invention which are as described under the summary of the invention can be produced by reacting a compound of the formula wherein and Alk, R and R have the same significance as above in an organic solvent, preferably under exclusion of water with about equimolecular quantities of the corresponding dicarboxylic anhydride or dicarboxylic acid ester halide (a) by heating, if desired under reflux and if desired in the presence of a base or (b) in the presence of equimolecular quantities of a tertiary organic nitrogen base, if desired at an elevated temperature to produce the corresponding onium salt and recovering the desired product in a known manner.
  • solvents such as acetone or halogenated hydrocarbons may be employed.
  • Aromatic, aliphatic or mixed aromatic-aliphatic tertiary organic nitrogen bases such as, for instance, pyridine,
  • collidine, trialkyl amines, preferably, triethyl amine, may
  • the reaction mixture for example, may be heated under reflux, if desired, and after cooling down the solution is shaken out with weakly alkaline water, slightly acidifying the aqueous phase whereupon the triazine compound precipi tates out.
  • the starting piperazino, morpholino or alkanol amino substituted triazines can be produced by the methods analogous to those disclosed in US. application Ser. No. 623,548, filed Mar. 16, 1967, by reacting trichloromethyl substituted triazines with alkanol amines, morpholine or piperazine.
  • novel compounds according to the invention are useful as antiinfiammatory antiphlogistic agents and particularly as analgesics.
  • the compounds for example, upon oral administration to mice in doses of 300 to 400 mg./kg. have a strong analgesic action as determined by the mouse tail test according to Hatfner and their acute toxicity (LD between about 900 to 1700 mg./ kg.
  • the therapeutic index thereof is better than, for instance, that of phenacetin.
  • novel compounds may be enteral, for instance, in the form of pills, capsules tablets, dragees, suppositories, oily or aqueous solutions or suspensions, or parenteral as injectable aqueous or oily solutions or suspensions.
  • the single dosage for relief of pain may be between 1 and 500 mg. and may be administered one or more times a day.
  • EXAMPLE 2 34.2 g. (0.1 mol) of 2-trichlorornethyl-4-morpholino- 6-ethanolamino-s-triazine were heated to 50 C. in 150 ml. of dried ethyl acetate together with 10.5 g. (0.105 mol) of succinic acid anhydride and 10.6 g. (0.105 mol) of triethylamine, whereupon solution occurred. After 30 minutes the reaction mixture was permitted to cool down and then sh ken out. wi h Wat r whereupon the triethyl- 4 amine salt Went over into the aqeuous phase.
  • EXAMPLE 3 35.7 g. (0.1 mol) of 2-trichloromethyl-4-morpholino- 6-(Z-hydroxypropyl)-amino-s-triazine were heated under reflux for one hour in 150 ml. of ethyl acetate while stirring together with 10.5 g. (0.105 mol) of succinic acid anhydride and 10.6 g. 0.105 mol) of triethylamine. Solution occurred and after the reaction mixture had cooled down the salt was extracted with water and the free acid precipitated from the extract with the aid of HCl. 34 g. of 2 trichloromethyl-4-morpholino-6-(2-succinyl-oxypropyl) -amino-s-trazine were obtained. The melting point thereof was 160-161 C. and the yield was 74.5% of theory.
  • EXAMPLE 4 28.6 g. (0.08 mol) of 2-trichloromethyl-4-N'-methyl piperazino-6-ethanolamino-s-triazine were heated under reflux for 1 hour in ml. of ethyl acetate together with 8.4 g. (0.084 mol) of succinic acid anhydride. Solution occurred and after cooling the reaction mixture was shaken out with aqueous sodium bicarbonate.
  • the resulting aqueous phase was acidified to a pH of 6 by addition of HCl to precipitate the acid 2-trichloromethyl-4-N'-methylpiperazino-6- (2-succinyloxyethylamino -s-triazine NCH3 After filtering and washing with water the yield was 28 g. or 76% of theory. Its melting point was 156-161 C.
  • EXAMPLE 5 oho- -N N-OH3 was obtained from the salt by treatment with HCl.
  • the free acid had a melting point of 112118 C.
  • EXAMPLE 8 precipitated out. Yield: 42 g. or 92% of theory. Melting point: 200-202 C.
  • EXAMPLE 9 26.5 g. of 2-ethylamino-4-i-propylamino-6-piperazinos-tn'azine were stirred with 8 g. (0.1 mol) of pyridine in 150 ml. of methylene chloride. Then 10 g. of succinic acid anhydride were added thereto at room temperature over a period of /2 hour, whereupon the reaction mixture heated to 35 C. and solution occurred.
  • the pyridium salt which was formed was extracted from the methylene chloride solution with water and HCl added to the extract to adjust its pH to 6, whereupon 2-ethylamino-4-i-propylamino-6-N-succinylpiperazino-s-triazine H C zHN precipitated out. Yield: 32 g. or 8 8% of theory. Melting point: 1'83-l85 C.
  • EXAMPLE 10 26 g. of 2-chloro-4-morpholino-6-ethanolamino-s-triazine were stirred with 8 g. (0.1 mol) of pyridine in 200 ml. of ethylene chloride and 10 g. of succinic acid anhydride added. The mixture was allowed to stand overnight at room temperature. The pyridine salt produced was extracted with water and converted to the free acid with 6 H01. Yield: 24 g. or 67% of theory of 2-chloro-4-morpholine-6-succinyloxyethylamino-s-triazine NHCHr-CHz-O-CO-(CHzh-COOH Melting point: 173-178 C.
  • EXAMPLE 11 34.2 g. of 2-trichloromethyl-4-morpholino-6-ethylenediamine-s-triazine were stirred with 10.1 g. of triethylamine in 200 m1. of methylene chloride at room temperature. 10 g. of succinic acid anhydride were added thereto over a period of /2 hour while cooling to 25 C. After 2 hours the methylene chloride solution was extracted with water and the extract adjusted to a pH of 4 with HCl. 2- trichloromethyl 4 morpholino-6-N'-succinylethylene diamine-s-triazine precipitated out. Yield: 38 g. or 86% of theory. Melting point: 187l90 C.
  • EXAMPLE 12 35.7 g. of 2-trichloromethyl-4-morpholino-6-(2-hydroxypropyl) -amino-s-triazine were suspended in 200 ml. of ethyl acetate and refluxed for 1 hour with 12 g. of glutaric acid anhydride and 10.1 g. of triethylamine, whereupon solution occurred. The resulting salt was extracted with water and the aqueous extract adjusted to a pH of 6 with HCl, whereupon a syrupy product separated out which was then taken up in 150 ml. of methylene chloride. The resulting solution was boiled down and the residue stirred with 1:1 ether-hexane, whereupon crystallization occurred. Yield: 33 g. or 70% of theory of 2- trichloromethyl-4-morpholino-6-(2 oxyglutarylpropyl)- amino-s-triazine Melting point: 119-122 C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US640349A 1966-05-21 1967-05-22 2 - trichloromethyl - 4 - morpholino-6-(succinyloxy alkyl)amino - s - triazines and lower alkyl esters thereof Expired - Lifetime US3536709A (en)

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DED0050171 1966-05-21

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US (1) US3536709A (enExample)
BE (1) BE698747A (enExample)
CH (1) CH522658A (enExample)
DE (1) DE1670525A1 (enExample)
DK (1) DK119561B (enExample)
FR (1) FR7026M (enExample)
GB (1) GB1191465A (enExample)
IL (1) IL27910A (enExample)
NL (1) NL6706966A (enExample)
SE (1) SE336343B (enExample)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3697520A (en) * 1970-04-30 1972-10-10 Ciba Geigy Ag Triazine carboxylic acids and esters
US20150210652A1 (en) * 2013-03-13 2015-07-30 The United States Of America, As Represented By The Secretary Of The Army, On Behalf Of The Walter Substituted Triazines for Malaria Treatment and Chemoprophylaxis

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980350A (en) * 1988-02-25 1990-12-25 Merck & Co., Inc. Piperazinylalkylpyrimidines as hypoglycemic agents
EP0330263A1 (en) * 1988-02-25 1989-08-30 Merck & Co. Inc. Piperazinylalkylpyrimidines as hypoglycemic agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3697520A (en) * 1970-04-30 1972-10-10 Ciba Geigy Ag Triazine carboxylic acids and esters
US20150210652A1 (en) * 2013-03-13 2015-07-30 The United States Of America, As Represented By The Secretary Of The Army, On Behalf Of The Walter Substituted Triazines for Malaria Treatment and Chemoprophylaxis
US9334246B2 (en) * 2013-03-13 2016-05-10 The United States Of America, As Represented By The Secretary Of The Army, On Behalf Of The Walter Reed Army Institute Of Research Substituted triazines for malaria treatment and chemoprophylaxis
US9700562B2 (en) 2013-03-13 2017-07-11 The United States Of America, As Represented By The Secretary Of The Army, On Behalf Of The Walter Reed Army Institute Of Research Triazine compounds and compositions thereof and methods for treating malaria and chemoprophylaxis

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BE698747A (enExample) 1967-11-03
GB1191465A (en) 1970-05-13
DK119561B (da) 1971-01-25
NL6706966A (enExample) 1967-11-22
SE336343B (enExample) 1971-07-05
IL27910A (en) 1971-12-29
CH522658A (de) 1972-06-30
DE1670525A1 (enExample) 1971-12-09
FR7026M (enExample) 1969-06-09

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