US3549757A - Use of 2-morpholino - 4 - amino-6-substituted-s-triazines for inducing depressant effects in animals - Google Patents

Description

United States Patent USE OF Z-MORPHOLINO 4 AMINO-G-SUBSTI- TUTED-s-TRIAZINES FOR INDUCING DEPRES- SANT 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-impart of abandoned applications Ser. No. 498,099 and Ser. No. 498,118, both filed Oct. 19, 1965. This application Mar. 27, 1968, Ser- Int. Cl. A61k 27/00 US. Cl. 424-248 12 Claims ABSTRACT OF THE DISCLOSURE Use of 2-morpholino-4-amino-6-substituted-s-triazines for inducing depressant effects in animals.

This application is a continuation-inpart of copending applications Ser. Nos. 498,099 and 498,118, both filed Oct. 19, 1965 and both now abandoned.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel method for inducing depressant effects in mammals. These depressant effects include sedative, analgesic, muscle relaxant, anticonvulsant and tranquilizing efiects. 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-morpholino- 4 amino-6-substituted-s-triazines. The provisions for supplying the art with novel pharmaceutical and veterinary compositions capable of inducing neurological depressant effects in mammals forms another object.

These and other objects are accomplished by administering to a mammal an efiective dosage of a 2-morpholino- 4-amino-6-substituted-s-triazine of the formula wherein Y is -NRR in which R is hydrogen or alkyl of 1-3 carbon atoms and R is alkyl of l-4 carbon atoms, phenyl or chlorophenyl; and R and R together with the nitrogen atom can represent piperidino or lower alkyl-substituted piperidino; and

Z is

ice

in which R is hydrogen, alkyl of l-3 carbon atoms,

where alkyl is of l-3 carbon atoms and m is 0-3, or -alkylene-CN Where alkylene is of 2-4 carbon atoms;

S alkyleneN O where alkylene is of l-3 carbon atoms;

| H alkylene-NGRa where R is -NH or alkyl of 1-3 carbon atoms and alkylene is of l-3 carbon atoms;

CN; SCN; OR where R, is alkyl of 1-3 carbon atoms;

IIIHz 'C:NOR5

where R is hydrogen or alkyl of 1-3 carbon atoms;

where R is alkyl of 1-3 carbon atoms and alkylene is of 1-3 carbon atomsand salts thereof.

Representative species of the above s-triazines are:

( 1 2-morpholino-4-ethylamino-6-piperazino-s-triazine (2) 2-morpholino-4-tert-butylamino-6-piperazinos-triazine (3 2-morpholino-4-dimethylamino-6-piperazinos-triazine (4) 2-morpholino-4-anilino-6-piperazino-s-triazine (5 2-morpholino-4- (2-chloroanilino -6-p-iperazinos-triazine (6) 2-morpholino-4-ethy1amino-6-(4-methylpiperazino)- s-triazine hydrochloride (7) 2-morpholino-4-ethylamino-6-(4-(ethoxycarbony1) piperazino -s-triazine (8) 2-morpholino-4-ethylamino-6-(4-(ethoxycarbonylmethyl) piperazino)-s-triazine (9) 2-morpholino-4- (2,6-dimethylpiperidino) -6- 4- (2- cyanoethyl) piperazino)-s-triazine 10) 2-morpholino-4- (2-chloroanilino) -6- (4- (2-cyanoethyl) piperazino) -s-triazine 1 l) 2-morpholino-4-ethylamino- 6-chloro-s-triazine (l2) 2-morpholino-4-methylamino-fi-chloro-s-triazine l3 2-morpholino-4-diethylamino-6-chloro-s-triazine (14) Z-morpholino-4-dimethylamino-6-chloro-s-triazine 15 2-morpholino-4-propylamino-6-chloro-s-triazine (16) 2-morpholino-4-isopropylamino-6-(Z-morpholinoethyl) -thio-s-triazine l7 2-morpholino-4-anilino-6-ureidomethyl-s-triazine 18 2-morpholino-4-diethylamino-6-acetamidomethy1- s-triazine (19) 2-morpholino-4-tert-butylamino-6-acetamidomethyl-s-triazine (20) 2-morpholino-4-methylamino-6-cyano-s-triazine (21) 2-morpholino4'diethylamino6 cyano-s-triazine (22) 2-morpholino4-diethylamino6-thiocyanato-striazine (23) 2morpholino4-methylamino-6-methoxy-s-triazine (24) 2-morpholino4-ethylamino-6-methoxy-s-triazine (25) 2-morpholino-4-dimethylamino-6-methoxy-striazine (26) 2-morpholino-4-diethylamino-6-methoxy-striazine (27 2-morpholino4-isopropylamino-6-(l-amino-l- (hydroxyimino) methyl)-s-triazine (28) 2-morpholino-4-ethylamino-6- 1-amino-1-(ethoxyimino) methyl)-s-triazine (29) 2morpholino-4-isopropylamino-6-(1-amino-1- ethoxyimino) methyl)-s-triazine (30) 2-morpholino-4-tert-butylamino-6-( l-amino-l- (ethoxyimino) methyl)-s-triazine (31) 2-morpholino-4-dimethylamino-6-piperidino-s triazine (32) 2morpholino-4-ethylamino6-thiocarbarnoyl-striazine (33) 2-morpholino4-ethylamino-6-benzylidineiminooxys-triazine (34) 2-morpholino-4-ethylamino-6-(N-Z-hydroxyethyl- N-methylamino 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, methyl cellulose, dimethyl sulfoxide or other liquid excipients known in the pharmaceutical and veterinary formulation art.

Any of the above preparations may contain the triazines of the invention or may contain in addition other pharmaceutically active agents. For example, for tropical 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 milligrams per kilogram of body weight be 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 dose-can contain from about 1 percent to about 95 percent of active material, based upon the tital 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 may be prepared by any of the conventional methods known in the art for preparing these types of s-triazines. The following descriptions are illustrative of some of the methods that may be used.

The starting material for the s-triazines disclosed herein is cyanuric chloride. From this s-triazine the various compounds of the invention may be prepared by replacement of the chloro groups with the various substituents depicted in Formula I.

Thus, the amino substituents, i.e., morpholino, NRR, piperazino and N-alkyl piperazino and N (R alkylene-OH may be readily introduced by the known reactions of replacing the chloro substituents of chloro-s-triazines by reaction with the respective amines as described in Elderfield, R. C. Heterocyclic Compounds N.Y., J. Wiley and Sons, Inc. 1961, pp. 669671.

The cyanoalkylpi erazino-s-triazines are readily prepared by reaction of a piperazino-s-triazine with a cyanoalkene at moderate temperatures in a lower alkanol solvent in the presence of a catalytic amount of benzyltrimethylammonium hydroxide.

The N-alkoxycarbonylpiperazinos-triazines may be prepared by reacting a piperazino-s-triazine with an alkyl chloroformate (Cl-C(O)O-alkyl) in a halogenated hydrocarbon solvent in the presence of triethylamine. The remaining N-substituted piperazino-s-triazines, those substituted by an alkoxycarbonylalkyl group, may be prepared by recating a piperaZino-s-triazine with an appropriate alkyl ester of a chloroalkanoic acid in an organic solvent such as an ether at moderate temperatures.

The morpholinoalkylthio groups may be introduced by reacting a mercapto-s-triazine with a N-chloroalkylmorpholine hydrochloride in an aqueous solution of sodium hydroxide.

The ureidoalkyl substituents (R is -NH may conveniently be introduced by reaction of an appropriate aminoalkyl-s-triazine with potassium cyanate using water for the reaction media. The alkylcarbonylaminoalkyl substituents (R is alkyl) may be prepared by hydrogenating a cyano or cyanoalkyl-s-triazine in the presence of the ap propriate alkanoic acid anhydride.

The cyano substituents can be introduced by the methods described in US. 3,234,225 while the SCN group may be introduced by the methods described in US 3,120,468.

The alkoxy substituents may also be introduced by methods known in the art, e.g., by refluxing a chloro-striazine in a reaction media of a lower alkanol and acetone with a solution of sodium in a lower alkanol.

The C(NH )=NOR group may be introduced (R is hydrogen) by refluxing a cyano-s-triazine with hydroxylamine hydrochloride in a lower alkanol diluent in the presence of an aqueous solution of sodium hydroxide. The C(NH )=NO-alkyl substituents may be prepared by heating a mixture of a cyano-s-triazine and an O-alkylhydroxylamine (H NOR where R is alkyl) in a lower alkanol solvent in the presence of hydrogen sulfide.

The thiocarbamoyl group (CSNH may be introduced 'by heating a mixture of a cyano-s-triazine, triethylamine and hydrogen sulfide in an ether diluent.

The benzylideneiminooxy substituent may be introduced by reacting a chloro-s-triazine with benzaldoxime in an organic diluent in the presence of a base such as triethylamine.

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 that is physiologically acceptable for administration to mammals. The hydrochloride salts are preferred.

The following examples illustrate some of the methods for preparing the s-triazines of the invention.

Example I 24 g. (0.1 mol) 2-ethylamino-4-chloro-6-morpholino-striazine and 25.8 g. (0.3 mol) piperazine, mixed in 100 ml. ethanol, were refluxed for 30 minutes. After distilling oil the ethanol, the residue was taken up in methylene chloride and washed with water. After distilling off the methylene chloride, stirring the residue in ether, 22.5 g. 2 ethylamino 4 piperazino 6 morpholino s triazine, M.P. 110-112 C., crystallized out.

Example II 24.35 g. (0.1 mol) 2-chloro-4-morpholino-6-ethylaminos-triazine was dissolved in a mixture of 150 ml. acetone and 50 ml. methanol and heated while a solution of 2.3 g. (0.1 mol) sodium in 50 ml. methanol was slowly added. The mixture was refluxed for 1 hour. After cooling, the salt was filtered out and the solution concentrated. The concentrate was taken up in methylene chloride and Washed with water. After drying, the solvent was removed, leaving 19.4 g. 2-methoxy-4-morpholino-6-ethylamino-striazine, M.P. 127-132 C.

Example III (a) To 18.45 g. (0.1 mol) cyanuric chloride, dissolved in 200 ml. methylene chloride, was slowly added with stirring at C., 22.6 g. (0.2 mol) of 2,6-dimethylpiperidine. After removing the precipitated dimethylpiperidine hydrochloride, 17.4 g. (0.2 mol) morpholine was added to the stirred solution at a temperature of 20 C. After 2 hours, the precipitated morpholine hydrochloride was filtered off, the solution washed with water, dried and concentrated. After washing the concentrate with ether and then drying, 21.2 g. 2-morpholino 4-chloro-6- (2,6-dimethylpiperidino)-s-triazine, M.P. 16875 C., was obtained.

(b) 31.15 g. (0.1 mol) of the product of 3(a) was gradually added to a boiling solution of 58.2 g. (0.3 mol) piperazine hexahydrate in 200 ml. ethanol and refluxed for 30 minutes. After cooling, the solution was filtered and concentrated. After the crystalline residue from the concentrate was washed with water and dried, there was obtained 27.5 g. 2 morpholino 4 piperazino-6-(2,6-dimethylpiperidino)-s-triazine, M.P. 14648 C.

Example IV 24.4 g. (0.1 mol) 2-morpholino-4-chloro--6-ethy1aminos-triazine was refluxed for 1 hour with 20 g. (0.2 mol) N- methylpiperazine in 200 ml. ethanol. After concentrating the solution, the concentrate was taken up with 200 ml. methylene chloride and washed with water. After drying and concentrating the solution, the sirupy residue was dissolved in ether and filtered. After introducing HCl gas into the sirupy residue, 25 g. of the hydrochloride of 2 morpholino-4-(N-methylpiperazino)-6-ethylamino-striazine, M.P. 230-38 C., was obtained.

Example V 100 g. 2-diethylamino-4-morpholino-6-cyano-s-triazine was added to 450 ml. acetic anhydride and hydrogenated on a Raney-Nickel catalyst at C. with hydrogen. The solution was evaporated to dryness, taken up with water and the pH adjusted to 9 with soda. The residue was filtered and the product, 2 diethylamino 4 morpholino-6-acetamidomethyl-s-triazine, M.P. 8890 C., was crystallized from isopropanol.

PREFERRED EMBODIMENTS While the s-triazines of Formula I show some depressant eifects in mammals, there are differences both quantitative and qualitative exhibited by individual members of the class. Especially preferred depressants because of their activity as analgesics, muscle relaxants, anticonvulsants, and/or tranquilizers are the s-triazine of the formula.

wherein R is alkyl of 1-4 carbon atoms, preferably ethyl, and R is hydrogen or alkyl of l-3 carbon atoms, preferably hydrogen; and Z is alkoxy of 1-2 carbon atoms, preferably methoxy, or piperazino; and salts thereof. Preferred s-triazines within this subclass are:

TABLE I Muscle relaxant- Anticonvulsant response (e) Tranquilization response (d) Maximal elec- Analgesic re- 1 ernici0us tro-shock seiz- Antistrychnine Approximate Approximate sponse intraperpreenlng antagure antagonism response ratio analgesic muscle relaxitoneal (0) Muscle relaxomsm based on based on ED50 based on ED dose0ral ant dose0ral analgesic rating ant ratlngat EDso 1.p. or 32 i.p. or i.p. or 180 mg./kg. Test compound 1 (a), mgJkg. (b), rug/kg. at 100 mg./kg. 100 mg./kg. i.p. mgJkg. i.p. nag/kg. i.p. i.p.

TABLE L Continued Muscle relaxant- Anticonvulsant response (e) Tranquilization response ((1) Maximal elec- Analgesic re- Pernicious tro-shock seiz- Antistrychnine Approximate Approximate spouse intraperpreening antagure antagonism response ratio analgesic muscle rclaxitoneal Muscle relaxonism based on based on ED 0 based on EDm dose-Oral ant dose-0ral analgesic rating ant rating at ED i.p. or 32 i.p. or 100 i.p. or 180 mg./kg. Test compound 1 (a), rug/kg. (b), mg./kg. at 100 rug/kg. 100 mg./kg. i.p. ing/kg. i.p. mgJkg. i.p. i.p.

1 Numbers correspond to numbered triazines in columns 2 and 3.

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 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 (LD Muscle relaxant response (b).As in (a) 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, flaccidity 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 ml. per kg. The results were obtained by evaluation similar to that described for the Approximate Analgesic DoseOral. The compounds were rated on a one plus to four plus scale. When 12 mice out of ten showed an analgesic response, a rating was assigned; indicated that 3-6 out of ten mice responded; indicated that 79 out of ten responded;

while a rating meant that all ten mice gave an analgesic response at the dosage tested.

Muscle relaxant-tranquilization response (d).The muscle relaxant effects, 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, J. G., et al., 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 com pulsive behavior was noted for a 10 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, ++=3-6 mice out of ten, +++=79 mice out of ten and ++++=10 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 effective response. These ED values were then translated into the +1 to +4 scale by the following criteria: ED values of 30100 mg./kg.=+, 10-30 mg./kg.=++, 3-10 mg./kg.= and 3 mg./

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 mean was considered an effective action. Anticonvulsant activity in these tests suggests skeletal muscle relaxation or efficacy against epileptic seizures. Effective antagonism of maximal electroshock seizure and antistrychnine activity are given on the same +1 to +4 scale as in (0). 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.=++, 10-30 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 ED 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 of 1-3 carbon atoms and R is alkyl of 1-4 carbon atoms, phenyl or chlorophenyl; and R and R together with the nitrogen atom can represent piperidino or lower alkyl-substituted piperidino; and

Z is

--N N-R2 in which R is hydrogen, alkyl of 1-3 carbon atoms,

where alkyl is of 1-3 carbon atoms and m is -3, or --alkyleneCN where alkylene is of 2-4 carbon atoms;

where alkylene is of 1-3 carbon atoms;

I II alkylene-N- C-R;

where R is -NH or alkyl of 1-3 carbon atoms and alkylene is of 1-3 carbon atoms; CN; -SCN;

-OR where R; is alkyl of 1-3 carbon atoms;

where R is hydrogen or alkyl of 1-3 carbon atoms;

where R; is alkyl of 1-3 carbon atoms and alkylene is of 1-3 carbon atoms; and salts thereof; and (b) a physiologically acceptable carrier, the percent by weight of (a) in the total formulation being from about one to 95.

2. The veterinary and pharmaceutical composition of claim 1 wherein Y is -NRR in which R is alkyl of l-4 carbon atoms and R is hydrogen or alkyl of 1-3 carbon atoms and Z is alkoxy of 1-2 carbon atoms or piperazino.

3. The veterinary and pharmaceutical composition of claim 2 wherein R is ethyl and R is hydrogen.

4. The veterinary and pharmaceutical composition of claim 3 wherein Z is methoxy.

5. The veterinary and pharmaceutical composition of claim 3 wherein Z is piperazino.

6. 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 wherein Y is NRR in which R is hydrogen or alkyl of 1-3 carbon atoms and R is alkyl of 1-4 carbon atoms, phenyl or chlorophenyl; and R and R together with the nitrogen atom can represent piperidino or lower alkyl-substituted piperidino; and

Z is 1 in which R is hydrogen, alkyl of 1-3 carbon atoms,

where alkyl is of 1-3 carbon atoms and m is 0-3, or alkylene-CN where alkylene is of 2-4 carbon atoms;

Salky1ene-N 0 where alkylene is of 1-3 carbon atoms;

l H alkyleneN-- GR3 'where R; is -NH or alkyl of 1-3 carbon atoms and alkylene is of 1-3 carbon atoms;

where R is alkyl of 1-3 carbon atoms and alkylene is of 1-3 carbon atoms; and salts thereof. 7. The rnethod of claim 5 wherein said compound is administered orally to said mammal.

8. Thefinethod of claim 6 wherein said compound is administefed parenterally to said mammal.

9. The method of claim 6 wherein Y is NRR in which Rjs alkyl of 1-4 carbon atoms and R is hydrogen 1 1 or alkyl of 1-3 carbon atoms and Z is alkoxy of 12 carbon atoms or piperazino.

10. The method of claim 9 wherein R is ethyl and R is hydrogen.

11. The method of claim 10 wherein Z is methoxy. 12. The method of claim 10 wherein Z is piperazino.

References Cited UNITED STATES PATENTS 2,909,419 10/1959 Gysin et a1. 260249.5

12 3,122,542 2/1964 Knusli et a1. 260-2498 3,202,499 8/1965 Knusli 260-2499 FOREIGN PATENTS 1,329,306 4/1963 France 260-2495 OTHER REFERENCES Chemical Abstracts, 43, 1426 C 1949).

ALBERT T. MEYERS, Primary Examiner D. M. STEPHENS, Assistant Examiner