US3549755A - Use of 2-trichloromethyl-4-morpholinoor piperazino-6-substituted-s-triazines for inducing depressant effects in animals - Google Patents

Use of 2-trichloromethyl-4-morpholinoor piperazino-6-substituted-s-triazines for inducing depressant effects in animals Download PDF

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US3549755A
US3549755A US716291A US3549755DA US3549755A US 3549755 A US3549755 A US 3549755A US 716291 A US716291 A US 716291A US 3549755D A US3549755D A US 3549755DA US 3549755 A US3549755 A US 3549755A
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triazine
trichloromethyl
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Jiro K Kodama
James R Albert
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Shell USA Inc
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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

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  • This invention relates to a method of inducing depressant effects in animals using certain s-triazines. More particularly it relates to the use of certain s-triazines as analgesics, muscle relaxants, anticonvulsants and tranquilizers and to pharmaceutical and veterinary compositions containing such triazines.
  • the provisions for supplying the art with novel pharmaceutical and veterinary compositions capable of inducing neurological depressant efiects in mammals forms another object.
  • R is hydrogen or hydroxyalkyl of 1-3 carbon atoms
  • alkylene is alkylene of 1-3 carbon atoms
  • Z is --NH-alkylene-OH where alkylene is alkylene of 1-4 carbon atoms
  • alkylene is alkylene of 1-4 carbon atoms and alkyl is alkyl of 1-3 carbon atoms;
  • R is hydrogen or alkyl of 1-3 carbon atoms and R is alkyl of 1-3 carbon atoms, phenyl or nitrophenyl;
  • R is carboxyalkyl of 2-5 carbon atoms, alkyl of 1-3 carbon atoms, phenyl, carboxy-walkenyl of 35 carbon atoms, dialkylamino of 2-6 carbon atoms or alkoxycarbonylalkyl of 37 carbon atoms and alkylene is alkylene of up to 3 carbon atoms;
  • alky1 where each alkyl is of 1-3 carbon atoms;
  • alkylene and alkyl have from 13 carbon atoms
  • alkylene is of 2-4 carbon atoms; and the salts thereof.
  • Preparations for administration of the active agent in unit dose form can be powders, compressed tablets, or a powder enclosed in a suitable capsule of absorbable material such as gelatin.
  • the powders or compressed tablets may also comprise suitable excipients and/ or diluents such as starch, lactose, stearic acid, magnesium stearate, deXtrin or polyvinylpyrrolidone.
  • Preparations for topical application may be in the form of a liquid, a powder, a salve, or as an aerosol.
  • Preparations for parenteral administration may be sterile solutions or suspensions in liquids such as water,
  • any of the above preparations may contain the tri azines of the invention or may contain in addition other pharmaceutically active agents.
  • topical 4- application it may be desirable to include a germicide and/or a fungicide.
  • the unit dosage or therapeutically effective quantity of the triazines used according to this invention as analgesics, muscle relaxants, anticonvulsants and/ or tranquilizers can vary over wide limits.
  • analgesics, muscle relaxants, anticonvulsants and/ or tranquilizers can vary over wide limits.
  • for oral or parenteral administration in some cases, as little as 0.01 milligram of the active material per kilogram of body weight can be effective in the reduction of pain or in effecting sedation and muscle relaxation, while seldom will a dosage in excess of about 500 miligrams per kilogram of body weight he required.
  • the effective dosage will be from about 1.0 to 200 milligrams per kilogram of body weight, while for parenteral administration, the effective dosage will be from about 0.10 to about 100 milligrams per kilograms of body weight.
  • Each dosage unit formeach capsule, tablet, ampoule, or prescribed dosecan contain from about 1 percent to about percent of active material, based upon the total weight of the formulation and preferably contains from about 2.5 percent to about 50 percent of the active material, on the same basis.
  • the therapeutic agents used according to the invention can be administered either prior to or after the onset of the condition to be treated, such as when they are used as: analgesics for the amelioration of pain; motor depressants or tranquilizers to relieve nervous tension; central depressants to reduce hyperexcitability and induce sedation, or as muscle relaxants for relief from pain and discomfort of disorders involving muscle spasms.
  • the s-triazines of this invention can be prepared by conventional methods known in the art for preparing these types of striazines. The following descriptions are illustrative of some of the methods that may be used.
  • the morpholino, piperazino and N-hydroxyalkyl and N-alkyl piperazine substituents are introduced by reacting the appropriate trichloromethyl-s-triazine with an equimolar amount of morpholine, piperazine, N-hydroxyalkyl piperazine or N-alkyl piperazine in a solution of a lower alkanol at moderate temperatures.
  • reaction of the piperazino-s-triazine in dioxane with the appropriate chloroalkyl benzene By reaction of the piperazino-s-triazine in dioxane with the appropriate chloroalkyl benzene,
  • R is alkylene
  • the phenyl is introduced.
  • reaction of the piperazino s-triazine in a solution of acetic acid with KOCN introduces the carbamoyl R group.
  • the corresponding N-hydroxyalkylcarbamoyl group is introduced by first preparing the N -ethoxycarbonyl piperazino s-triazine by reacting the piperazino s-triazine, dissolved in a halogenated hydrocarbon solvent, with ClC(O) OC H in the presence of pyridine and then by reaction of this precursor in a lower alkanol solvent with the appropriate alkanolamine.
  • the 2,2,2-trichloro-l-iminoethyl group is introduced by reacting the piperazino s-triazine with trichloroacetonitrile.
  • the last Y substituent, -alkylene- II O-C -alkylene-O O OH is introduced by reacting the N-hydroxyalkyl piperazino s-triazine in a halogenated hydrocarbon diluent with the appropriate dicarboxylic acid anhydride.
  • the alkoxycarbonyloxyalkyl-s-triazines may be prepared by the methods described in U.S. 3,264,293.
  • the striazines described therein are then used to prepare the striazines of this invention.
  • the hydrazino-s-triazines may be prepared by replacement of the trichloromethyl substituent by reacting the appropriate trichloromethyl s-triazine at room temperature with a molar excess of hydrazine hydrate. Reaction of the appropriate hydrazino-s-triazine with a suitable ketone or aldehyde at moderate temperatures yields the alkylidene-hydrazino s-triazine. Similar treatment with an aliphatic aldehyde in a lower alkanol solvent yields the phenylalkylidenehydrazino.
  • the s-triazines containing the O NH-alkylene-O( iR radical are readily prepared by reacting an appropriate hydroxyalkylamino-s-triazine with the appropriate monoor dicarboxylic acid anhydride, benzoyl chloride, alkendioic acid anhydride, N,N-dialkylcarbamoyl chloride or mono alkyl ester of a dicarboxylic acid chloride R is alkylene and R is alkyl).
  • the reaction of the monoor dicarboxylic acid anhydrides with the appropriate hydroxyalkylamino-s-triazine is preferably carried out in an ethyl acetate reaction media in the presence of triethylamine.
  • the alkylamino substituents are preferably introduced by reaction of the appropriate trichloromethyl-s-triazine in a lower alkanol solvent with a primary alkylamine.
  • the chloroalkylamino groups are introduced by conventional technique such as reacting an appropriate hydroxyalkylamino-s-triazine with thionyl chloride.
  • N,N-dialkylaminoal koxy groups are introduced by reacting an appropriate trichloromethyl-s-triazine with an N,N-dialkylaminoalkanol in the presence of sodium hydroxide.
  • the a-hydroxyalkyl-s-triazines may be prepared by reacting an alkoxycarbonyloxyalkyls-triazine in a lower alkanol solvent at the reflux temperature with a barium alkanolate prepared by reacting barium hydroxide in hot alkanol, preferably methanol, and separating the carbonate from the barium alkanolate.
  • the N-I-I-alkylene-NHC(O)alkyl group may be introduced by replacement of a trichloromethyl group with an alkylenediamino group by reacting the trichloromethyl-s-triazine with a molar excess of an alkylenediamine; and then reacting this aminoalkylamino-s-triazine with the appropriate alkanoic acid anhydride in the presence of pyridine.
  • the last group of s-triazines those containing the morpholinoalkyl group may be prepared by reacting an alkenyl-s-triazine in a lower alkanol solvent with morpho line.
  • the salts of the s-triazines of the invention are prepared by the conventional method of reacting the s-triazine with an inorganic or organic acid.
  • examples of such acids are sulfuric, phosphoric, hydrochloric, sulfamic, benzylsulfonic, maleic, fumaric, succinic, tartaric and the like.
  • the salt-forming acid should be one that is physiologically acceptable for administration to mammals.
  • the hydrochloride salts are preferred.
  • EXAMPLE I 30 g. of 2,4-bis-trichloromethyl-6-morpholino-s-triazine were suspended in 200 ml. of methanol and 9.12 g. of ethanol amine and 0.5 g. of Na dissolved in 50 ml. of methanol added thereto. The mixture was heated under reflux until solution occurred (about 10 minutes) and such heating continued for about a further 50 minutes. The solution was cooled on ice, whereby Z-trichloromethyl-4-ethanolamino 6 morpholino s triazine crystallized out in almost analytically pure form. After it was filtered off, washed with water and dried, 22 g. of the product with a melting point of 162164 C. were obtained. The yield was 86.3 of theory.
  • the starting material of this example was produced by dissolving 1 mol of tris-trichloromethyl-s-triazine in about 1 liter of methanol and adding 1 mol of morpholine to such solution at 10 C. Upon addition of the amine the solution warmed up to about 4050 C. When the reaction solution cooled down the 2,4-bis-trichloromethyl-6- morpholino-s-triazine precipitated out and Was filtered off and Washed. The yield was about 75% of theory. The melting point was 160165 C.
  • EXAMPLE 111 31.25 g. (0.1 mol) of 2-trichloromethyl-4-piperazino-6- hydrazino-s-triazine was heated at the reflux temperature for 1 hour with 10.6 g. (0.1 mol) of benzaldehyde in 300 ml. of methanol. After the methanol was distilled off and the residue washed with water, the product, 2-trichloro methyl-4-piperazino-6-benzylidenehydrazino s triazine, M.P. 185-190" C. was collected in 87.4% yield.
  • EXAMPLE IV 40 g. (0.1 mol) of 2-piperazino-4,6-bis-(trichloromethyl)-s-triazine was suspended in g. hydrazine hydrate at room temperature for 2 days. The product, 2-trichloromethyl 4 piperazino 6 hydrazino s-triazine, M.P. 167169 C., was separated from the mixture and washed with water.
  • EXAMPLE V 34.15 g. (0.1 mol) of 2-trichloromethyl-4-piperazino-6- (2-hydroxyethylamino)-s-triazine was slowly added to a stirred mixture of 3.65 g. HCl gas in 300 ml. of methanol. After 2 hours, the crystals of 2-trichloromethyl-4-piperazino-6-(2-hydroxyethylamino)-s-triazine hydrochloride, M.P. 210 C., were separated out and dried.
  • EXAMPLE VI 34.2 g. (0.1 mol) of 2-trichloromethyl-4-morpholino- 6-ethanolamino s triazine were heated to 50 C. in 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 shaken out with water whereupon the triethylamine salt went over into the aqueous phase.
  • Muscle relaxant, Anticonvulsant response (0) tranquilization response (1) Analgesic Maximal response Pernicious electroshock Approximate intraperipreening seizure Antistryehnine Approximate muscle toueal (1:), Muscle antagonism antagonism response ratio analgesic relaxant analgesic relaxant based on E1350 based on ED based on EDm dose, oral (a), dose, oral (b), rating ratmg at ilp. or 32 i.p. or i.p. or Text compound 1 mgJkg. mg./kg. at 100 mgJkg. 100 mg./kg.i.p. mg./kg. i.p. mgJkg. i.p. mg./kg. i.p.
  • Analgesic response (a) The presence of an analgesic effect was identified as an absence of a struggling or phonating response to a manual pinch of the tail of treated mice.
  • the laboratory white mice for each treatment were placed in individual compartments. The mice were orally intubated with the test compound at the dosage of 500 milligrams per kilogram, and 15 minutes, 1 hour, 2 hours, 4 hours and 24 hours after treatment a pinch of the tail was applied to each mouse. Any compound inducing an analgesic response in 50 percent of the mice at any of these test intervals was considered active in this test. Some of the compounds were tested at lower dosages.
  • mice were orally intubated with the test compound and the muscle relaxant effects of the compounds were evaluated.
  • the procedure for assessing skeletal muscle relaxant activity involves an evaluation of passivity, fiaccidity and pinnal reflex blockage.
  • Passivity is defined as an absence of the struggle behavior of the animal when manipulated manually and may indicate skeletal muscle relaxation, central depression, tranquilization, paralysis, or anesthesia.
  • Flaccidity is measured by the decreased tonus of skeletal musculature and may indicate myorelaxant activity, central depression, or paralysis.
  • the pinnal reflex is tested by touching the inner aspects of the ear with a fine wire to elicit a characteristic ear twitch. An impairment of this reflex suggests an inhibition of polysynaptic reflexes.
  • Analgesic response-intraperitoneal The analgesic response was determined in laboratory white mice by injection of the triazines under test at an intraperitoneal dosage of 100 mg. per kg. The results were obtained by evaluation similar to that described for the Approximate Analgesic Doseral. The compounds were rated on a one plus to four plus scale. When l-2 mice out of ten showed an analgesic response, a rating was assigned; indicated that 36 out of ten mice responded; indicated that 7-9 out of ten responded; while a rating meant that all ten mice gave an analgesic response at the dosage tested.
  • Muscle relaxanttranquilization response (d) The muscle relaxant eflects, as expressed by passivity, flaccidity and pinnal reflex blockage, were assessed in laboratory mice injected intraperitoneally with 100 mg./ kg. of the test compound as in (b). In addition the tranquilizing effects of the compounds under test were evaluated by the pernicious preening test ,(Wilfon, I. G. et a1. Fed Proc. 19:20, 1960). The pernicious preening behavior was elicited by painting the rear of the mice with a pilocohesive dye. A violent unremitting tearing of the stiff, cohering strands of hair constitutes the pernicious preening behavior.
  • Anticonvulsant response The test procedures used were maximal electroshock and antistrychnine assay methods. The test compound was intraperitoneally injected into laboratory mice and after 30 minutes the anticonvulsant activity was measured. The technique employed in the maximal electroshock method was essentially that of Swinyard, E. A., J. Amer. Pharm. Assoc. 38:201 (1949). The mice were subjected to an alternating current stimulus, about equal to three times the current necessary to produce maximal seizures, and prevention of the hindlimb tonic extensor phase was considered to be an effective anticonvulsant action.
  • mice were intraperitoneally injected with the test compound and then were challenged with a lethal intraperitoneal dose of strychnine sulfate. Increase in survival time against the lethal action of strychnine of greater than three standard deviations of the control means was considered an effective action.
  • Anticonvulsant activity in these tests suggests skeletal muscle relaxation or eflicacy against epileptic seizures.
  • Eifective antagonism of maximal electroshock seizure and antistrychnine activity are given on the same +1 to +4 scale as in (c).
  • the antistrychnine activities for the individual triazines were also determined in either of two ways. Some are based on the response ratio at mg./kg. while the others on the B13 values.
  • the criteria for translating the ED values to the +1 to +4 scale is the same as for the maximal electroshock seizure test.
  • a depressant veterinary and pharmaceutical composition comprising a (a) compound of the formula wherein Y is wherein R is hydrogen; alkyl of 1-3 carbon atoms;
  • alkylene-O--alkyleneC O OH where alkylene is alkylene of 13 carbon atoms
  • Z is NH-alkylene-OH where alkylene is alkylene of 1-4 carbon atoms
  • alkylene is alkylene of 1-4 carbon atoms and alkyl is alkyl of 1-3 carbon atoms
  • NI-I-N CR R where R is hydrogen or alkyl of 1-3 carbon atoms and R is alkyl of 1-3 carbon atoms, phenyl or nitrophenyl;
  • alkylene is of 2-4 carbon atoms; and the salts thereof; and (b) a physiologically acceptable carrier, the percent by weight of (a) in the total formulation being from about one to about 95.
  • Y is -N or N N-R where R is hydrogen, alkyl of 1-3 carbon atoms or hydroxyalkyl of 1-3 carbon atoms; and Z is NHR OH where R is alkylene of 1-4 carbon atoms;
  • R is carboxyalkyl of 2-5 carbon atoms and alkylene is of 1-3 carbon atoms; or dialkylamino of 2-4 carbon atoms; and salts thereof.
  • Y is and Z is NHR OH.
  • Y is N O or -N N-R wherein R is hydrogen; alkyl of 1-3 carbon atoms; hy-
  • alkylene is alkylene of 1-4 carbon atoms and alkyl is alkyl of 1-3 carbon atoms;
  • NHN CH R where R is hydrogen or alkyl of 1-3 carbon atoms and R is alkyl of 1-3 carbon atoms, phenyl or nitrophenyl;
  • R is carboxyalkyl of 2-5 carbon atoms, alkyl of l-3 carbon atoms, phenyl, carboxy-u-alkenyl of 3-5 carbon atoms, dialkylamino of 2-6 carbon atoms or alkoxycarbonylalkyl of 3-7 carbon atoms and alkylene is alkylene of up to 3 carbon atoms;
  • alkyl is alkyl of 1-3 carbon atoms
  • alkylene is alkylene of 1-3 carbon atoms
  • each alkyl is of l-3 carbon atoms
  • alkylene and alkyl have from 1-3 carbon atoms
  • alkylene is of 24 carbon atoms; and the salts 18 Th h d f l i 12 h i Yi thereof. 5 12.
  • the method of claim 11 wherein Yis-N 0 or --N NR 19.
  • R is hydrogen U and Z is Z-hydroxyethylamino.
  • R is y r alkyl f 1 carbon atoms r 20.
  • R is hydrogen droxyalkyl of 1-3 carbon atoms; and Z is --NHR -OH d Z i benzylidenehydrazino
  • R is alkylene of 1-3 carbon atoms; 21.
  • R is hydrogen and Z is NHNH References Cited TNHNH; UNITED STATES P'ATENTS where alkyl is of 1-3 carbon atoms;
  • R is carboxyalkyl of 2-5 carbon atoms and alkyl- FOREIGN PATENTS ene is of 1-3 carbon atoms; or dialkylamino of 2-4 5 carbon atoms; and alts thereof France 13.
  • PATENTS ene is of 1-3 carbon atoms; or dialkylamino of 2-4 5 carbon atoms; and alts thereof France 13.
  • the method of claim 12 wherein said compound is administered orally to said mammal.
  • OTHER REFERENCES 14 14.
  • said compound Chemical Abstracts, 1426 M 9 9)- is administered parenterally to said mammal.

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Description

United States Patent O USE OF 2-TRICHLOROMETHYL- t-MORPHOLINO- OR PIPERAZINO-6-SUBSTITUTED-s-TRIAZINES FOR INDUCING DEPRESSANT EFFECTS IN ANIMALS Jiro K. Kodama and James R. Albert, Modesto, Calif., assignors to Shell Oil Company, New York, N.Y., a corporation of Delaware No Drawing. Continuation-in-part of applications Ser. No.
498,099, and Ser. No. 498,118, Oct. 19, 1965. This application Mar. 27, 1968, Ser. No. 716,291
Int. Cl. A61k 27/00 US. Cl. 424-248 22 Claims ABSTRACT OF THE DISCLOSURE Use of 2-trichloromethyl-4-morpholinoor -piperazino- 6-substituted-s-triazines for inducing depressant effects in animals.
This application is a continuation-in-part of copending applications Ser. Nos. 498,099 and 498,118, both filed Oct. 19, 1965 and both now abandoned.
BACKGROUND OF THE INVENTION This invention relates to a method of inducing depressant effects in animals using certain s-triazines. More particularly it relates to the use of certain s-triazines as analgesics, muscle relaxants, anticonvulsants and tranquilizers and to pharmaceutical and veterinary compositions containing such triazines.
A considerable number of naturally occurring alkaloids and synthetic chemicals are available as useful anlgesics, anticonvulsants and muscle relaxants. Repeated administration of many such analgesics creates the potential danger of drug addiction. The need for effective analgesics which minimize the hazards of drug addiction has long been recognized.
SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel method for inducing depressant efiects in mammals. These depressant effects include sedative, analgesic, muscle relaxant, anticonvulsant and tranquilizing effects. Another object of the invention is to provide a novel method of pain control with minimum hazard of drug addiction. Yet another object is to provide a novel method for inducing depressant effects in mammals with certain 2-trichloromethyl-4-morpholinoor -piperazino-6-substituteds-triazines. The provisions for supplying the art with novel pharmaceutical and veterinary compositions capable of inducing neurological depressant efiects in mammals forms another object.
These and other objects are accomplished by administering to a mammal an effective dosage of a 2-trichloromethyl-4-morpholinoor -piperazino-6-sub'stituted-s-triazine of the formula i Y-C wherein Y is N or N wherein R is hydrogen, alkyl of 1-3 carbon atoms, bydroxyalkyl of 1-3 carbon atoms,
3,549,755 Patented Dec. 22, 1970 Where m is 1-3,
wherein R is hydrogen or hydroxyalkyl of 1-3 carbon atoms,
0 0 C13, or -alkyle11e-0 ll-alkylene-O O OH wherein alkylene is alkylene of 1-3 carbon atoms; and Z is --NH-alkylene-OH where alkylene is alkylene of 1-4 carbon atoms;
i -alkylene-O- C 0 alkyl where alkylene is alkylene of 1-4 carbon atoms and alkyl is alkyl of 1-3 carbon atoms;
where R is hydrogen or alkyl of 1-3 carbon atoms and R is alkyl of 1-3 carbon atoms, phenyl or nitrophenyl;
where R, is carboxyalkyl of 2-5 carbon atoms, alkyl of 1-3 carbon atoms, phenyl, carboxy-walkenyl of 35 carbon atoms, dialkylamino of 2-6 carbon atoms or alkoxycarbonylalkyl of 37 carbon atoms and alkylene is alkylene of up to 3 carbon atoms;
NH-alkyl where alkyl is alkyl. of 1-3 carbon atoms;
CCl
NH-alkylene-Cl where alkylene is alkylene of 1-3 carbon atoms;
O-alky1ene-N-(alkyl) where alkylene and alkyl have from 1-3 carbon atoms;
)11 C (alky1) where each alkyl is of 1-3 carbon atoms;
where alkylene and alkyl have from 13 carbon atoms;
and
where alkylene is of 2-4 carbon atoms; and the salts thereof.
Representative species of the above s-triazines are:
(12) 2-trichloromethyl-4-piperazino-6-isopropylidenehydrazino-s-triazine (13) 2-trichloromethyl-4-piperazino-6-p-nitrobenzylidenehydrazino-s-triazine 14) 2-trichloromethyl-4-piperaZino-6-benzylidenehydrazino-s-triazine (15) 2-trichloromethyl-4-(4-methylpiperazino) -6- hydrazino-s-triazine (16) 2-trichl0r0methyl-4-( 4-( 2-hydroxyethyl) piperazino)-6-hydrazin0-striazine 17) 2-trichloromethyl-4-(4-benzylpiperazino)-6- hydrazino-s-triazine l8) Z-trichloromethyl-4-piperazino-6-hydrazinos-triazine 19) 2-trichloromethyl-4- 4-methylpiperazino -6- (carboxypropionyloxy) ethylamino)-s-triazine (20) 2-trichloromethyl-4-morpholino-6-((carboxypropionyloxy) ethylamino) -s-triazine (21 2-trichloromethyl-4-morpholino-6-( (carboxypro pionyloxy) -2-methylethylamino -s-triazine (22) 2-trichloromethyl-4-morpholino-6-((carboxybutyryloxy -2-methylethylamino -s-triazine (23) 2-trichloromethyl-4-morpholino-6-acetoxyethylamino-s-triazine (24) 2-trichloromethyl-4-morpholino-6-benzoyloxyethylamino-s-triazine (25) 2-trichloromethyl-4-morpholino-6-(2-(carboxyacryloyloxy) ethylamino -s-triazine (26) 2-trichloromethyl-4-morpholino-6-N,N-dimethy1- carbamoyloxyethylamino-'s-triazine (27) 2-trichloromethyl-4-morpholino-6- carbomethoxypropionyloxyethylamino-s-triazine (28) 2-trich1oromethy1-4-(4-(Z-hydroxyethyl) piperazino -6-ethylamino-s-triazine (29) 2-trichloromethyl-4-(4-(carboxyethylcarbonyloxyethyl piperazino -6-ethylamino-s-triazine (30) 2-trichloromethyl-4-(4-carbamoylpiperazino)- 6-trichloromethyl-s-triazine (31) 2-trichloromethyl-4-(4-(2,2,2-trichloro-liminoethyl -piperazino -6-trichloromethyl-s-triazine (3 2) 2-trichloromethyl-4-morpholino-6- 2- chloroethylamino -s-triazine (33 2-trichloromethyl-4-morpholino-6-(2-dimethylaminoethoxy -s-triazine (34) 2-trichloromethyl-4-morpho1ino-6-( l-hydroxyl-methylethyl) -s-triazine (35) 2-trichloromethyl-4-morpholino-6-(2- acetamidoethylamino -s-triazine (36) 2-trichloromethyl-4-morpholino-6-(2- (morpholino ethyl) -s-triazine Compositions according to the present invention also comprise a pharmaceutical carrier which may either be solid material or a liquid. Preparations for oral administration can be liquids or solids or any combination of these forms, such as syrups, elixirs, powders, capsules, or
tablets. Preparations for administration of the active agent in unit dose form can be powders, compressed tablets, or a powder enclosed in a suitable capsule of absorbable material such as gelatin. The powders or compressed tablets may also comprise suitable excipients and/ or diluents such as starch, lactose, stearic acid, magnesium stearate, deXtrin or polyvinylpyrrolidone.
Preparations for topical application may be in the form of a liquid, a powder, a salve, or as an aerosol. Preparations for parenteral administration may be sterile solutions or suspensions in liquids such as water,
physiological saline, benzyl alcohol, ethyl oleate, methylcellulose, dimethyl sulfoxide or other liquid excipients known in the pharmaceutical and veterinary formulation art.
Any of the above preparations may contain the tri azines of the invention or may contain in addition other pharmaceutically active agents. For example, for topical 4- application it may be desirable to include a germicide and/or a fungicide.
The unit dosage or therapeutically effective quantity of the triazines used according to this invention as analgesics, muscle relaxants, anticonvulsants and/ or tranquilizers can vary over wide limits. For oral or parenteral administration in some cases, as little as 0.01 milligram of the active material per kilogram of body weight can be effective in the reduction of pain or in effecting sedation and muscle relaxation, while seldom will a dosage in excess of about 500 miligrams per kilogram of body weight he required. In general, for oral administration, the effective dosage will be from about 1.0 to 200 milligrams per kilogram of body weight, while for parenteral administration, the effective dosage will be from about 0.10 to about 100 milligrams per kilograms of body weight. Each dosage unit formeach capsule, tablet, ampoule, or prescribed dosecan contain from about 1 percent to about percent of active material, based upon the total weight of the formulation and preferably contains from about 2.5 percent to about 50 percent of the active material, on the same basis. Of course, it is possible to administer the therapeutics without the use of a pharmaceutical carrier.
The therapeutic agents used according to the invention can be administered either prior to or after the onset of the condition to be treated, such as when they are used as: analgesics for the amelioration of pain; motor depressants or tranquilizers to relieve nervous tension; central depressants to reduce hyperexcitability and induce sedation, or as muscle relaxants for relief from pain and discomfort of disorders involving muscle spasms.
Preparation The s-triazines of this invention can be prepared by conventional methods known in the art for preparing these types of striazines. The following descriptions are illustrative of some of the methods that may be used.
The starting material for most of the s-triazines of this invention is 2,4,6 tris-trichloromethyl-s-triazine. From this s-triazine the various compounds of the invention are prepared by replacement of the trichloromethyl groups with the various groups depicted in Formula I.
Thus, the morpholino, piperazino and N-hydroxyalkyl and N-alkyl piperazine substituents are introduced by reacting the appropriate trichloromethyl-s-triazine with an equimolar amount of morpholine, piperazine, N-hydroxyalkyl piperazine or N-alkyl piperazine in a solution of a lower alkanol at moderate temperatures. By reaction of the piperazino-s-triazine in dioxane with the appropriate chloroalkyl benzene,
R is alkylene), in the presence of pyridine, the phenylis introduced. Likewise reaction of the piperazino s-triazine in a solution of acetic acid with KOCN introduces the carbamoyl R group. The corresponding N-hydroxyalkylcarbamoyl group is introduced by first preparing the N -ethoxycarbonyl piperazino s-triazine by reacting the piperazino s-triazine, dissolved in a halogenated hydrocarbon solvent, with ClC(O) OC H in the presence of pyridine and then by reaction of this precursor in a lower alkanol solvent with the appropriate alkanolamine. The 2,2,2-trichloro-l-iminoethyl group is introduced by reacting the piperazino s-triazine with trichloroacetonitrile. The last Y substituent, -alkylene- II O-C -alkylene-O O OH is introduced by reacting the N-hydroxyalkyl piperazino s-triazine in a halogenated hydrocarbon diluent with the appropriate dicarboxylic acid anhydride.
Within the Z or third category of substituents the hydroxyalkylamino group is introduced by replacement of a trichloromethyl group by reaction of the appropriate trichloromethyl s triazine with a hydroxyalkylarnine (H N-alkylene-OH) in the presence of a catalytic amount of an alkali metal alcoholate in a lower alkanol solvent at moderate temperatures.
The alkoxycarbonyloxyalkyl-s-triazines may be prepared by the methods described in U.S. 3,264,293. The striazines described therein are then used to prepare the striazines of this invention.
The hydrazino-s-triazines may be prepared by replacement of the trichloromethyl substituent by reacting the appropriate trichloromethyl s-triazine at room temperature with a molar excess of hydrazine hydrate. Reaction of the appropriate hydrazino-s-triazine with a suitable ketone or aldehyde at moderate temperatures yields the alkylidene-hydrazino s-triazine. Similar treatment with an aliphatic aldehyde in a lower alkanol solvent yields the phenylalkylidenehydrazino.
The s-triazines containing the O NH-alkylene-O( iR radical are readily prepared by reacting an appropriate hydroxyalkylamino-s-triazine with the appropriate monoor dicarboxylic acid anhydride, benzoyl chloride, alkendioic acid anhydride, N,N-dialkylcarbamoyl chloride or mono alkyl ester of a dicarboxylic acid chloride R is alkylene and R is alkyl). The reaction of the monoor dicarboxylic acid anhydrides with the appropriate hydroxyalkylamino-s-triazine is preferably carried out in an ethyl acetate reaction media in the presence of triethylamine.
The alkylamino substituents are preferably introduced by reaction of the appropriate trichloromethyl-s-triazine in a lower alkanol solvent with a primary alkylamine.
The chloroalkylamino groups are introduced by conventional technique such as reacting an appropriate hydroxyalkylamino-s-triazine with thionyl chloride.
The N,N-dialkylaminoal koxy groups are introduced by reacting an appropriate trichloromethyl-s-triazine with an N,N-dialkylaminoalkanol in the presence of sodium hydroxide.
The a-hydroxyalkyl-s-triazines may be prepared by reacting an alkoxycarbonyloxyalkyls-triazine in a lower alkanol solvent at the reflux temperature with a barium alkanolate prepared by reacting barium hydroxide in hot alkanol, preferably methanol, and separating the carbonate from the barium alkanolate.
The N-I-I-alkylene-NHC(O)alkyl group may be introduced by replacement of a trichloromethyl group with an alkylenediamino group by reacting the trichloromethyl-s-triazine with a molar excess of an alkylenediamine; and then reacting this aminoalkylamino-s-triazine with the appropriate alkanoic acid anhydride in the presence of pyridine.
The last group of s-triazines, those containing the morpholinoalkyl group may be prepared by reacting an alkenyl-s-triazine in a lower alkanol solvent with morpho line.
The salts of the s-triazines of the invention are prepared by the conventional method of reacting the s-triazine with an inorganic or organic acid. Examples of such acids are sulfuric, phosphoric, hydrochloric, sulfamic, benzylsulfonic, maleic, fumaric, succinic, tartaric and the like. The salt-forming acid should be one that is physiologically acceptable for administration to mammals. The hydrochloride salts are preferred.
The following examples will serve to illustrate the preparation of the compounds of this invention.
EXAMPLE I 30 g. of 2,4-bis-trichloromethyl-6-morpholino-s-triazine were suspended in 200 ml. of methanol and 9.12 g. of ethanol amine and 0.5 g. of Na dissolved in 50 ml. of methanol added thereto. The mixture was heated under reflux until solution occurred (about 10 minutes) and such heating continued for about a further 50 minutes. The solution was cooled on ice, whereby Z-trichloromethyl-4-ethanolamino 6 morpholino s triazine crystallized out in almost analytically pure form. After it was filtered off, washed with water and dried, 22 g. of the product with a melting point of 162164 C. were obtained. The yield was 86.3 of theory.
The starting material of this example was produced by dissolving 1 mol of tris-trichloromethyl-s-triazine in about 1 liter of methanol and adding 1 mol of morpholine to such solution at 10 C. Upon addition of the amine the solution warmed up to about 4050 C. When the reaction solution cooled down the 2,4-bis-trichloromethyl-6- morpholino-s-triazine precipitated out and Was filtered off and Washed. The yield was about 75% of theory. The melting point was 160165 C.
EXAMPLE II 178.5 g. (0.4 mol) 2-(1-methyl 1 (ethoxycarbonyloxy) ethyl)-4,6 bis-(trichloromethyl)-s-triazine was dissolved in 200 ml. of hot methanol and 35 g. (0.4 mol) of morpholine was added. After cooling, 128 g. of 2-(amethyla-ethoxycarbonyloxy)-ethyl 4 morpholine 6- trichloromethyl-s-triazine, M.P. 106109 C., was ob tained.
EXAMPLE 111 31.25 g. (0.1 mol) of 2-trichloromethyl-4-piperazino-6- hydrazino-s-triazine was heated at the reflux temperature for 1 hour with 10.6 g. (0.1 mol) of benzaldehyde in 300 ml. of methanol. After the methanol was distilled off and the residue washed with water, the product, 2-trichloro methyl-4-piperazino-6-benzylidenehydrazino s triazine, M.P. 185-190" C. was collected in 87.4% yield.
EXAMPLE IV 40 g. (0.1 mol) of 2-piperazino-4,6-bis-(trichloromethyl)-s-triazine Was suspended in g. hydrazine hydrate at room temperature for 2 days. The product, 2-trichloromethyl 4 piperazino 6 hydrazino s-triazine, M.P. 167169 C., was separated from the mixture and washed with water.
EXAMPLE V 34.15 g. (0.1 mol) of 2-trichloromethyl-4-piperazino-6- (2-hydroxyethylamino)-s-triazine was slowly added to a stirred mixture of 3.65 g. HCl gas in 300 ml. of methanol. After 2 hours, the crystals of 2-trichloromethyl-4-piperazino-6-(2-hydroxyethylamino)-s-triazine hydrochloride, M.P. 210 C., were separated out and dried.
EXAMPLE VI 34.2 g. (0.1 mol) of 2-trichloromethyl-4-morpholino- 6-ethanolamino s triazine were heated to 50 C. in 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 shaken out with water whereupon the triethylamine salt went over into the aqueous phase. Upon adjustment of the pH of the aqueous solution to 4 the 2-trichloromethyl-4-morpholino 6 (2 succinyl oxyethylamino)-s-triazine is obtained in free acid form. After 8 where alkyl is of 1-3 carbon atoms, preferably methyl;
washing and drying the yield was 38 g. or 86% of theory E (melting point 176178 C.). Nelkylenc-O- R2 PREFERRED EMBODIMENTS where R is carboxyalkyl of 2-5 carbon atoms, preferably While the s-triazines of Formula I show some depres- YP PY alkylene 15 015.13 carPon atoms sant effects in mammals, there are differences both quan- 10 Preferably z'methylethylenei or filalkylamlno of 2 4 titative and qualitative exhibited by individual members Carbon atoms, Preferably ethylamlno; and Salts thereof- Of the class p i y Preferred1 deplressants bec'ause 1 Preferred s-triazines within the subclass are: their activity as ana gesics, muse e re axants, antlconvu sants, and/ or tranquilizers are the s-triazine of the z'mcilloromelhyi'4'morphohno'6-(Z'hydmxyethyL formula am1no)-s-tr1az1ne,
Z-trichloromethyl-4-rnorphol1no-6-(2hydroxypropyl- 7 amino -s-triazine, 0 2-trichloromethy1-4-piperazino-6- Z-hydroxyethylamino s-triazine, hydrochloride,
| 2-trichloromethyl-4-piperazino-6-benzylidenehydrazino- YC C-C C13 s-trlazlne,
N 2-trichloromethyl-4-(4-methylp1peraz1no)-6-hydraz1nowherein Y is sitriazine 2-tr1chl0romethyl-4-p1peraz1no-6-hydraz1no-s-tr1azme, O or 2-trichloromethyl-4-morpholino-6-(l-hydroxy-1-methyl ethyl) -s-triazine, where R is hydrogen, alkyl of 1-3 carbon atoms, or 2-trichlorornethyl-4-rnorpholino-6-((carboxybutyryloxy)- hydroxyalkyl of 1-3 carbon atoms, preferably hydro- 2-methylethylamino)-s-triazine, gen, methyl or 2-hydroxyethyl, and 2-trichlor0methyl-4-(4-(Z-hydroxyethyl)-piperazino)-6- Z is -NHR OH where R is alkylene of l4 carbon ethylamino-s-triazine,
atoms, preferably NHCH CH -OH, 2-trichl0romethyl-4-piperazino-6-(Z-hydroxyethylamino)- OH s-triazine, and NH H CH 2-trichlor0rnethyl-4-morpholino-6-(1,1-dimethyl-2- E 3 O hydroxyethylamino)-s-triazine. N or H (CHQFCHZ H The following examples are presented to illustrate certain pharmacological responses induced by triazine com- NH CH2 CHPCHZOH positions of the invention. These examples should in no on way be regarded as limiting the scope of the invention.
| -NH-N=CH NHNH O-(alkyl)g 40 The results of the various pharmacological responses tested are shown in Table I.
TABLE I Muscle relaxant, Anticonvulsant response (0) tranquilization response ((1) Analgesic Maximal response Pernicious electroshock Approximate intraperipreening seizure Antistryehnine Approximate muscle toueal (1:), Muscle antagonism antagonism response ratio analgesic relaxant analgesic relaxant based on E1350 based on ED based on EDm dose, oral (a), dose, oral (b), rating ratmg at ilp. or 32 i.p. or i.p. or Text compound 1 mgJkg. mg./kg. at 100 mgJkg. 100 mg./kg.i.p. mg./kg. i.p. mgJkg. i.p. mg./kg. i.p.
o 0 0 +4 ++-l 0 0 5 "6 o 0 i 5 "6 0 0 0 0 2 2 2 0 0 o 0 0 0 0 0 0 0 0 0 -r+ o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 +1 "6 0 0 0 0 1 Numbers correspond to numbered triazines in 001s. 2 and 3. z 32 mgJkg.
Analgesic response (a) The presence of an analgesic effect was identified as an absence of a struggling or phonating response to a manual pinch of the tail of treated mice. The laboratory white mice for each treatment were placed in individual compartments. The mice were orally intubated with the test compound at the dosage of 500 milligrams per kilogram, and 15 minutes, 1 hour, 2 hours, 4 hours and 24 hours after treatment a pinch of the tail was applied to each mouse. Any compound inducing an analgesic response in 50 percent of the mice at any of these test intervals was considered active in this test. Some of the compounds were tested at lower dosages.
While the exact safety factor has not been evaluated for all compounds of the invention, it has been found that the effective analgesic dose of the triazines of the invention is considerably lower than the toxic dose 50)- Muscle relaxant response (b) As in (2) above, mice were orally intubated with the test compound and the muscle relaxant effects of the compounds were evaluated. The procedure for assessing skeletal muscle relaxant activity involves an evaluation of passivity, fiaccidity and pinnal reflex blockage. Passivity is defined as an absence of the struggle behavior of the animal when manipulated manually and may indicate skeletal muscle relaxation, central depression, tranquilization, paralysis, or anesthesia. Flaccidity is measured by the decreased tonus of skeletal musculature and may indicate myorelaxant activity, central depression, or paralysis. The pinnal reflex is tested by touching the inner aspects of the ear with a fine wire to elicit a characteristic ear twitch. An impairment of this reflex suggests an inhibition of polysynaptic reflexes.
Analgesic response-intraperitoneal (c) The analgesic response was determined in laboratory white mice by injection of the triazines under test at an intraperitoneal dosage of 100 mg. per kg. The results were obtained by evaluation similar to that described for the Approximate Analgesic Doseral. The compounds were rated on a one plus to four plus scale. When l-2 mice out of ten showed an analgesic response, a rating was assigned; indicated that 36 out of ten mice responded; indicated that 7-9 out of ten responded; while a rating meant that all ten mice gave an analgesic response at the dosage tested.
Muscle relaxanttranquilization response (d) The muscle relaxant eflects, as expressed by passivity, flaccidity and pinnal reflex blockage, were assessed in laboratory mice injected intraperitoneally with 100 mg./ kg. of the test compound as in (b). In addition the tranquilizing effects of the compounds under test were evaluated by the pernicious preening test ,(Wilfon, I. G. et a1. Fed Proc. 19:20, 1960). The pernicious preening behavior was elicited by painting the rear of the mice with a pilocohesive dye. A violent unremitting tearing of the stiff, cohering strands of hair constitutes the pernicious preening behavior. Thirty minutes after injection, the pilocohesive dye was applied and the presence or absence of the compulsive behavior was noted for a minute interval. The ratings for the muscle relaxant response are based upon the scale given in (0). Effective antagonism of pernicious preening is shown with the same scale as in (c). That is, +=1-2 mice out of ten, ++=36 mice out of ten, +'++=79 mice out of ten and +++'+=l0 mice out of ten responded. Some of these values for the individual triazines were determined at a dosage of 32 mg./kg. while the others were determined on the basis of ED values, the dose at which 50 percent of the treated animals exhibit an eflective response. These ED values were then trans- 10 lated into the +1 to +4 scale by the following criteria: ED values of 30-100 mg./kg.:+, 10-30 mg./kg.=++, 3-10 mg./kg.=+'++ and 3m g./kg.=++
Anticonvulsant response (e) The test procedures used were maximal electroshock and antistrychnine assay methods. The test compound was intraperitoneally injected into laboratory mice and after 30 minutes the anticonvulsant activity was measured. The technique employed in the maximal electroshock method was essentially that of Swinyard, E. A., J. Amer. Pharm. Assoc. 38:201 (1949). The mice were subjected to an alternating current stimulus, about equal to three times the current necessary to produce maximal seizures, and prevention of the hindlimb tonic extensor phase was considered to be an effective anticonvulsant action. In the antistrychnine assay, the mice were intraperitoneally injected with the test compound and then were challenged with a lethal intraperitoneal dose of strychnine sulfate. Increase in survival time against the lethal action of strychnine of greater than three standard deviations of the control means was considered an effective action. Anticonvulsant activity in these tests suggests skeletal muscle relaxation or eflicacy against epileptic seizures. Eifective antagonism of maximal electroshock seizure and antistrychnine activity are given on the same +1 to +4 scale as in (c). Some of these values for the individual triazines in the maximal electroshock seizure test were determined at a dosage of mg./kg. while the others were determined on the basis of ED values, the dose at which 50 percent of the treated animals exhibited an effective response. These ED values were then translated into the +1 to +4 scale by the following criteria: ED values of 100300 mg./kg.=+, 30 100 mg./kg.=++, l0-30 mg./kg.=+++ and 10 mg./ kg.=++++. The antistrychnine activities for the individual triazines were also determined in either of two ways. Some are based on the response ratio at mg./kg. while the others on the B13 values. The criteria for translating the ED values to the +1 to +4 scale is the same as for the maximal electroshock seizure test.
We claim as our invention.
1. A depressant veterinary and pharmaceutical composition comprising a (a) compound of the formula wherein Y is wherein R is hydrogen; alkyl of 1-3 carbon atoms;
hydroxyalkyl of 1-3 carbon atoms;
0 ll 1 C- 0013; or alkylene-O--alkyleneC O OH where alkylene is alkylene of 13 carbon atoms; and Z is NH-alkylene-OH where alkylene is alkylene of 1-4 carbon atoms;
II -a1ky1ene- 0- 0- O-alkyl 11 where alkylene is alkylene of 1-4 carbon atoms and alkyl is alkyl of 1-3 carbon atoms; NI-I-N=CR R where R is hydrogen or alkyl of 1-3 carbon atoms and R is alkyl of 1-3 carbon atoms, phenyl or nitrophenyl;
where alkylene is of 2-4 carbon atoms; and the salts thereof; and (b) a physiologically acceptable carrier, the percent by weight of (a) in the total formulation being from about one to about 95. 2. The veterinary and pharmaceutical composition of claim 1 wherein Y is -N or N N-R where R is hydrogen, alkyl of 1-3 carbon atoms or hydroxyalkyl of 1-3 carbon atoms; and Z is NHR OH where R is alkylene of 1-4 carbon atoms;
(3H NHNHZ; C-(alkyl) where alkyl is of 1-3 carbon atoms;
where R is carboxyalkyl of 2-5 carbon atoms and alkylene is of 1-3 carbon atoms; or dialkylamino of 2-4 carbon atoms; and salts thereof. 3. The veterinary and pharmaceutical composition of claim 2 wherein Y is and Z is NHR OH.
4. The veterinary and pharmaceutical composition of claim 3 wherein Z is 2-hydroxyethylamino.
5. The veterinary and pharmaceutical composition of claim 3 wherein Z is 2-hydroxypropylamino.
6. The veterinary and pharmaceutical composition of 7. The veterinary and pharmaceutical composition of claim 6 wherein R is hydrogen and Z is 2-hydroxyethylamino.
8. The veterinary and pharmaceutical composition of claim 6 wherein R is hydrogen and Z is benzylidenehydrazino.
9. The veterinary and pharmaceutical composition of claim 6 wherein R is methyl and Z is NHNH 10. The veterinary and pharmaceutical composition of claim 6 wherein R is hydrogen and Z is NHNH 11. A method of inducing a depressant response in mammals comprising administering to said mammal in need thereof an effective dosage of a compound of the formula a it YC 0-0011;
wherein Y is N O or -N N-R wherein R is hydrogen; alkyl of 1-3 carbon atoms; hy-
droxyalkyl of 1-3 carbon atoms;
o NI-IR' wherein R is hydrogen or hydroxyalkyl of 1-3 carbon atoms;
where m is 1-3;
NH (%0 C13 0 -alkylene-Oi -alkylene-c O 011 where alkylene is alkylene of 1-3 carbon atoms; and Z is -NH-alkylene-OH where alkylene is alkylene of l-4 carbon atoms;
0 -alkylcue-O( T O-alkyl Where alkylene is alkylene of 1-4 carbon atoms and alkyl is alkyl of 1-3 carbon atoms;
NHN=CH R where R is hydrogen or alkyl of 1-3 carbon atoms and R is alkyl of 1-3 carbon atoms, phenyl or nitrophenyl;
Where R is carboxyalkyl of 2-5 carbon atoms, alkyl of l-3 carbon atoms, phenyl, carboxy-u-alkenyl of 3-5 carbon atoms, dialkylamino of 2-6 carbon atoms or alkoxycarbonylalkyl of 3-7 carbon atoms and alkylene is alkylene of up to 3 carbon atoms;
-NH-alkyl where alkyl is alkyl of 1-3 carbon atoms;
CCl
NH-alklene-Cl where alkylene is alkylene of 1-3 carbon atoms;
O-alkyleneN-(alkyl) where alkylene and alkyl have from 1-3 carbon atoms;
where each alkyl is of l-3 carbon atoms;
where alkylene and alkyl have from 1-3 carbon atoms;
13 14 and 16. The method of claim 15 wherein Z is Z-hydroxyethylamino. -alkylene-N 17. The method of claim 15 wherein Z is Z-hydroxypropylamino.
Where alkylene is of 24 carbon atoms; and the salts 18 Th h d f l i 12 h i Yi thereof. 5 12. The method of claim 11 wherein Yis-N 0 or --N NR 19. The method of claim 18 wherein R is hydrogen U and Z is Z-hydroxyethylamino. where R is y r alkyl f 1 carbon atoms r 20. The method of claim 18 wherein R is hydrogen droxyalkyl of 1-3 carbon atoms; and Z is --NHR -OH d Z i benzylidenehydrazino,
where R is alkylene of 1-3 carbon atoms; 21. The method of claim 18 wherein R is methyl and Y Z is NHNH NHN=OH 15 22. The method claim 18 wherein R is hydrogen and Z is NHNH References Cited TNHNH; UNITED STATES P'ATENTS where alkyl is of 1-3 carbon atoms;
20 2,909,419 10/1959 Gysin et a1. 260249.5 3,122,542 2/1964 Knusli et a1 260-2493 N-alkylene-O-CR 3, 02,499 8/ 1965 Knusli 260 -249.9
Where R is carboxyalkyl of 2-5 carbon atoms and alkyl- FOREIGN PATENTS ene is of 1-3 carbon atoms; or dialkylamino of 2-4 5 carbon atoms; and alts thereof France 13. The method of claim 12 wherein said compound is administered orally to said mammal. OTHER REFERENCES 14. The method of claim 12 wherein said compound Chemical Abstracts, 1426 M 9 9)- is administered parenterally to said mammal.
1s. The method of claim 12 wherein Y is ALBERT MEYERS: Pnmary Exammer N O D. M. STEPHENS, Assistant Examiner 11.5. C1. X.R.
and Z is NHR OH. 424-249
US716291A 1968-03-27 1968-03-27 Use of 2-trichloromethyl-4-morpholinoor piperazino-6-substituted-s-triazines for inducing depressant effects in animals Expired - Lifetime US3549755A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0356413A1 (en) * 1988-08-16 1990-02-28 U C B, S.A. 2-Amino-4-morpholino-6-propyl-1,3,5-triazines
EP0356412A1 (en) * 1988-08-16 1990-02-28 U C B, S.A. Use of 2-amino-4-morpholino-6-propyl-1,3,5-triazines in the preparation of a medicament for the treatment of cognitive and mental disorders
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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6384032B1 (en) 1999-06-17 2002-05-07 Shionogi Bioresearch Corp. Inhibitors of IL-12 production
US6680315B2 (en) * 2000-06-15 2004-01-20 Synta Pharmaceuticals Corp. Triazine compounds
JP4851337B2 (en) * 2003-11-10 2012-01-11 シンタ ファーマシューティカルズ コーポレーション Heteroaryl hydrazone compounds

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2909419A (en) * 1959-10-20 Compositions and methods for influenc-
FR1329306A (en) * 1962-07-19 1963-06-07 Geigy Ag J R 2.4.6-substituted s-triazines salts and their applications
US3122542A (en) * 1959-05-06 1964-02-25 Geigy Ag J R Method for the preparation of 2, 4-diamino-6-fluoro-s-triazines
US3202499A (en) * 1960-11-02 1965-08-24 Geigy Ag J R Herbicidal compositions and method for inhibiting the growth of plants therewith

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2909419A (en) * 1959-10-20 Compositions and methods for influenc-
US3122542A (en) * 1959-05-06 1964-02-25 Geigy Ag J R Method for the preparation of 2, 4-diamino-6-fluoro-s-triazines
US3202499A (en) * 1960-11-02 1965-08-24 Geigy Ag J R Herbicidal compositions and method for inhibiting the growth of plants therewith
FR1329306A (en) * 1962-07-19 1963-06-07 Geigy Ag J R 2.4.6-substituted s-triazines salts and their applications

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0356413A1 (en) * 1988-08-16 1990-02-28 U C B, S.A. 2-Amino-4-morpholino-6-propyl-1,3,5-triazines
EP0356412A1 (en) * 1988-08-16 1990-02-28 U C B, S.A. Use of 2-amino-4-morpholino-6-propyl-1,3,5-triazines in the preparation of a medicament for the treatment of cognitive and mental disorders
US4956367A (en) * 1988-08-16 1990-09-11 U C B S.A. 2-amino-4-morpholino-6-propyl-1,3,5-triazines
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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