United States Patent (15) 3,679,798 Culik et al. (45) July 25, 1972

54) COMPOSITION COMPRISING ARYLAMNOOXAZOLINE AND (3) ( > or ANTICHLOLIGENERICAGENT / (72) Inventors: Rudolf Culik, 214 LaFayette St., Kennett Square, Pa. 19348; Jurg A. Schneider, 520 Rothbury Road, Wilmington, Del. 19808 (4) 4 R. 73) Assignee: E. I. du Pont de Nemours and Company, Wilmington, Del. --- o--R -NH-C 22 Filed: Feb. 28, 1964 N

(21) Appl. No.: 348,291 N--R3 (5) l; (52) U.S. Cl...... 424/265,424/247, 424/251, O-C-R1 424/263, 424/267, 424/272,260/307 D, 260/307 F /

(51 Int. Cl...... A61k 27/00 -NH-C (58) Field of Search... 260/553, 307; 167/65; 424/247, N--R: 424/251, 263,265,267, 272 R: and (56) References Cited UNITED STATES PATENTS (6) R 2,027,031 l/1936 Englelmann...... 260/44 A. X >-NH-C o--R 2,870, l 60 - 1 / 1959 Bloom...... 2601307 B N-d-R Primary Examiner-Leland A. Sebastian k Attorney-Herbert W. Larson where in each of formulas (1) through (6) R, R, R and Rare each separately selected from the group consisting of EXEMPLARY CLAIM hydrogen and alkyl of 1 through 4 carbons with the total number of carbons in these four substitutents being 8; where 17. A composition comprising one part by weight of an in each of formulas (1) through (5), through 3 hydrogen arylaminooxazoline and from about 0.5 to 30 parts by weight atoms of the moiety selected from the group consisting of of a centrally acting agent, said arylaminoox naphthyl, partially reduced naphthyl and indanyl can be azoline being selected from the group consisting of those of replaced with a member selected from the group consisting of the following formulas and pharmaceutically acceptable acid halogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 addition salts thereof: carbons, alkylthio of 1 through 4 carbons, trifluoromethyl and trifluoromethoxy; and where in formula (6) A is selected from (i) R the group consisting of hydrogen, alkyl of 1 through 4 car bons, alkoxy of l through 4 carbons and halogen; B is selected {- -NH-C o--R from the group consisting of alkyl of 1 through 4 carbons, al S koxy of 1 through 4 carbons and halogen; and C is selected N-C-R2 from the group consisting of hydrogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons halogen, alkylthio of 1 through 4 carbons, alkoxyalkyl wherein the alkoxy portion has 1 through 2 carbons and the alkyl portion has 1 through 2 car (2) { X O bons, alkylamino of 1 through 2 carbons, dialkylamino where each alkyl group has l through 2 carbons, trifluoromethyl and ( > trifluoromethoxy. 32 Claims, No Drawings 3,679,798 1. 2 COMPOSITION COMPRISING ARYLAMINOOXAZOLINE In addition to the above-mentioned , other AND ANTICHLOLIGENERICAGENT illustrative materials include homotropine, atroscine, eu This invention relates to pharmaceutical compositions use catropine, syntropan (amprotropine), pavatrine, banthine ful for both human and veterinary applications. More particu (), pro-banthine (propantheline), oxypenonium larly, this invention relates to synergistic utilization of one or (antrenyl), (monodral), diphenmethanil (pran more centrally acting anticholinergic substances and one or tal), mepiperphenidol (darstine), dicyclomine (bentyl), more of a class of central nervous system depressants. aminopentamide (centrine), dibutoline and the like. The disclosure herein should not be taken as a recommen As will be readily understood, the centrally acting an dation to use the disclosed invention in any way without full ticholinergics will most often be used in the form of an acid compliance with U.S. Food and Drug laws and other laws and 10 addition salt with anacid having a pharmaceutically accepta governmental regulations which may be applicable. ble anion. The term "pharmaceutically acceptable anion' has According to the present invention, an amazing synergism a definite meaning to one skilled in the art, namely, a non has been noted between a centrally acting anticholinergic and toxic anion of any of the simple acids commercially used to compounds in a class generically identified as 2-arylamino-2- neutralize basic medicinal agents. These acids include, for ex oxazolines. While the oxazolines themselves have activity, ample, hydrochloric, hydrobromic, hydriodic, sulfuric, suc some to a remarkable extent, as regulators and in particular cinic, maleic, tartaric, citric, glycolic, and others. The phar depressants of the central nervous system, we have now maceutical activity of the molecule is primarily but not neces discovered that, when used with a centrally acting an sarily exclusively a function of the cation, ticholinergic, the synergistic combination according to this in By way of further illustration of the salts of anticholinergic vention effects a profound action, producing a striking depres 20 agents, it can be mentioned that is preferably used as sion of central nervous system control of skeletal muscle as the hydrobromide, hydrochloride, methylbromide, methyl well as a striking loss of response to painful stimuli. This effect nitrate, salicylate, sulfate, atropine-sulfuric acid, valerate, au resembles a deep surgical anesthesia, producing uncon richloride, platinichloride, oxalate or picrate; as sciousness in the recipient in a very short time. the hydrobromide, hydrochloride, aurichloride, auribromide, Centrally acting anticholinergics are a well-recognized class 25 picrate, methylbromide, methylnitrate or aminoxide; of pharmacologically active substances. As is well known and Adephenine (Registered trademark) as the hydrochloride; be understood by pharmacologists, these anticholinergics can be nactyzine as the hydrochloride; benztropine as the naturally occurring or synthetic and are those substances methanesulfonate; as the hydrochloride or which act to inhibit and have a highly selective blocking action ethanedisulfonate; cycrimine as the hydrochloride; oxyphen on effector organs innervated by postganglionic 30 cyclimine as the hydrochloride; systral as the hydrochloride; nerves. As is known to personS skilled in this art, anticholiner and as the hydrochloride. gic agents containing a quaternary nitrogen moiety are of The second essential ingredient of the synergistic composi course not centrally acting. tions of the present invention is a 2-arylamino-2-oxazoline Perhaps the best known centrally acting anticholinergics are 35 having central nervous system depressant activity. Suitable 2 the natural occurring alkaloids of the belladonna plants. The arylamino-2-oxazolines include those of the following formu two most important of these alkaloids are atropine (dil las: ) and scopolamine (l-hyoscine) and these two materials are the preferred synergists according to the present (1) R invention because of their significantly outstanding synergiz ing action with the 2-arylamino-2-oxazolines. Also of special 40 importance because of outstanding activity are the centrally acting anticholinergic glycolates. However, the use of all centrally acting anticholinergic sub stances is intended to be embraced within the concept of the (2) present invention. Illustrative of such anticholinergics are the 45 following: Adephenine (Registered trademark), also identified as Trasentine (Registered trademark and 2 diethylaminoethyl diphenylacetate 50 k , also identified as beta-diethylaminoethyl (3) R benzilate benztropine, also identified as 3-diphenylmethyoxytropane o--R caramiphen, also identified as 1-phenylcyclopentane-car boxylic acid, diethylaminoethyl ester , also identified a0 1-hydroxy--phenyl 55 cyclopentaneacetic acid, 2-dimethylamino-ethyl ester cycrimine, also identified alpha-cyclopentyl-alpha-phenyl (4) 1-piperidinepropanol Ditran, also identified as N-ethyl-3-piperidyl phenyl cyclopentylglycolate 60 ethopropazine, also identified as 10-(2-diethylaminopropyl) , also identified as 1-methyl-1,4,5,6- (5) tetrahydro-2-pyrimidylmethyl alpha-cyclohexyl-alpha 65 phenylglycolate , also identified as N-ethyl-3-piperidyl diphen ylacetate systral, also identified as and beta dimethylaminoethyl (p-chloro-alpha-methylbenzhyd 70 and ryl)ether tricyclamol, also identified as and alpha (6) cyclohexyl-alpha-phenyl-1-pyrrolidine-propanol trihexphidyl, also identified as alpha-cyclohexyl-alpha phenyl-l-piperidinepropanol 75 3,679,798 3 4. In each of the aboVe formulas, R, R, R, and R are the In the foregoing procedures, the reaction between the same or different and can each be hydrogen or an alkyl group amine and isocyanate can conveniently be carried out in a of one through four carbons with the total number of carbons suitable inert organic solvent including both aromatic and in these four substituents being a maximum of eight. In the aliphatic hydrocarbon solvents. Halogenated, oxygenated or compounds of Formulas (1) through (5), the hydrogen atoms nitrated hydrocarbon solvents are useful. Representative sol of the naphthyl, the partially reduced naphthyl or the indanyl vents are benzene, carbon tetrachloride, ethylene groups may be replaced with substituents such as halogen, dichloride, chlorobenzene, , xylene, nitrobenzene and e.g., chlorine, bromine, fluorine and iodine, alkyl of one nitrotoluene. Temperatures in the range from 0 to 1 10°C. are through four carbons, alkoxy of one through four carbons, al suitable. kylthio of one through four carbons, trifluoromethyl and 10 Formation of the aryloxazoline is conveniently carried out trifluoromethoxy. Up through three such substituents can be by refluxing the urea in solution in a suitable solvent such as present. methanol, ethanol, propanol, butanol or preferably water, In Formula (6), A can be hydrogen, alkyl of one through with elimination of hydrogen bromide, hydrogen chloride, four carbons, and preferably one or two carbons, alkoxy of hydrogen iodide, methanesulfonic acid, p-toluenesulfonic acid one through four carbons, and preferably one or two carbons, 15 or halogen including chlorine, bromine, and fluorine; B can be or the like. Since the oxazolines are basic in nature, the alkyl of one through four carbons and preferably one or two liberated acid adds to the oxazoline to form an acid addition carbons, alkoxy of one through four carbons and preferably salt. The free base is liberated from the salt using an alkaline one or two carbons, or halogen including chlorine, bromine reagent such as ammonium hydroxide, sodium hydroxide, and fluorine; and C can be hydrogen, alkyl of one through four 20 sodium bicarbonate, calcium oxide or the like. carbons and preferably one or two carbons, alkoxy of one Useful synthesis techniques are described in Chem. through four carbons and preferably one or two carbons, Reviews, Vol. 44, pages 463-466 (1949). halogen including chlorine, bromine and fluorine, alkythio of By reference to the reaction described above, it can be seen one through four and preferably one or two carbons, alkoxyal that in the ordinary practice of the process of the invention, kyl wherein the alkoxy portion has one or two carbons and the 25 the oxazolines produced will be hydrobromides, alkyl portion has one or two carbons, alkylamino of one or two hydrochlorides, hydriodides, methanesulfonic acids or p carbons, dialkylamino where the alkyl group can be the same toluenesulfonic acids. These acids can be converted to other or different and each has one or two carbons, trifluoromethyl pharmaceutically acceptable acids by procedures well known or trifluoromethoxy. to those skilled in the art. One highly useful method comprises Preparation 30 contacting the acid addition salt with a basic anion exchange As will be noted, the compounds of Formula (1) are sub resin, for example, a highly basic compound such as the one stituted and unsubstituted 2-(1-naphthylamino)-2-oxazolines. available from Rohm & Haas Company under the name "Am These compounds and a method for their preparation are berlite IRA-400." This resin is a polyduaternary ammonium described in Bloom U.S. Pat. No. 2,81 1529 issued Oct. 29, compound which is prepared by chloromethylating a highly 1957. 35 cross-linked copolymer of styrene and divinylbenzene fol The compounds of Formula (2) are substituted and unsub lowed by treatment of the chloromethylated material with a stituted 2-(1,2,3,4-tetrahydro-1-naphthylamino)-2-ox tertiary amine such as trimethylamine. To prepare an acid ad azolines. A method for their preparation is described in bloom dition salt of this invention, for example, the citrate, the resin U.S. Pat. No. 2,870, 159 issued Jan. 20, 1959. is first contacted with an aqueous solution of citric acid The compounds of Formula (3) are substituted and unsub 40 whereupon an anion exchange takes place converting the stituted 2-(1-indanylamino)-2-oxazolines. A method for their quaternary halide to the citrate. The citrate resin is then con preparation is described in Bloom U.S. Pat. No. 2,870, 161 is tacted with an acid addition salt prepared as described above sued Jan. 20, 1959. and a further anion exchange takes place converting the acid The compounds of Formula (4) are substituted and unsub addition salt to the citrate and leaving the anion of the original stituted 2-(5,6,7,8-tetrahydro-1 naphthylamino)-2-oxazolines. 45 salt on the resin. The citrate salt can be recovered from the el The compounds of formula (5) are substituted and unsub uate by a number of methods such as evaporation or solvent stituted 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-ox precipitation. This same procedure can be used to prepare azolines. The compounds of Formula (5) are substituted and nitrates, sulfates, acetates and other acid addition salts. unsubstituted 2 -(4-indanylamino)-2-oxazolines. These com Illustrative of the compounds within the scope of Formula pounds of Formula (4) and (5) have remarkably superior ac 50 (1) above are the following: tivity as central nervous system depressants compared with 2-(3,4-dichoro-1-naphthylamino)-2-oxazoline the compounds of Formulas (2) and (3). The compounds of 2-(3-bromo-1-naphthylamino-2-oxazoline formulas (4) and (5) are claimed and their preparation 2-(4-ethyl-1-naphthylamino)-4,5-dimethyl-2-oxazoline described in copending U.S. patent application Ser. No. 55 2-(3,4,5-triiodo-1-naphthylamino)-2-oxazoline 313,756 filed Sept. 30, 1963 now U.S. Pat. No. 3,432,600, in 2-(3,4-bismethylthio-1-naphthylamino)-4-butyl-2-ox the name of John Harvey, Jr., and assigned to the same as azoline signee as that of the present invention. 2-(2,3,5-tri-sec-butoxy-1-naphthylamino)-2-oxazoline The compounds of Formula (6) are substituted 2-anilino-2- 2-(3,4-dimethoxy-1-naphthylamino)-4,5-diethyl-2-ox oxazolines. They are characterized by outstanding anti-hyper 60 azoline tensive and central nervous system depressant properties. 2-(4-tert-butylthio-1-naphthylamino)-2-oxazoline Their pharmaceutical use is claimed and their preparation 2-(3,4-diethoxy-1-naphthylamino)-4,5-dimethyl-2-ox described in copending U.S. patent application Ser. No. azoline 348,290 filed Feb. 28, 1964 now abandoned, in the name of 2-(4-isopropylthio-1-naphthylamino)-5-ethyl-2-oxazoline John Harvey, Jr., and assigned to the same assignee as that of 65 Illustrative of the compounds within the scope of Formula the present application. In the last-mentioned Harvey applica (2) above are the following: tion, a preferred group of compounds having unusual effec 2-(1,2,3,4-tetrahydro-3,4-dichloro-1-naphthylamino)-2-ox tiveness is also claimed. azoline Generally, the compounds of Formulas (1) through (6) are 2(1,2,3,4-tetrahydr-3,4,5-triiodo-1-naphthylamino)-2-ox crystalline solids, they can be readily prepared by reaction of 70 azoline the appropriately selected arylamine and an appropriate alkyl 2-(1,2,3,4,-tetrahydro-3,4,5-trimethyl-1-naphthyiamino)-2- isocyanate to form the corresponding N-aryl-N'-(beta-sub oxazoline stituted ethyl)urea, followed by heating in a suitable solvent to 2-(1,2,3,4-tetrahydro-3,4-dimethoxy-1-naphthylamino)- close the oxazoline ring. Alternatively, the urea can be 4,5-diethyl-2-oxazoline prepared by reaction between an appropriate aryl isocyanate 75 2-(1,2,3,4-tetrahydro-4-tetrahydroisopropyl-1- and an appropriate alkylamine followed by ring closure. naphthylamino)-5-ethyl-2-oxazoline 3,679,798 S 6 Illustrative of the compounds within the scope of Formula (3) above are the following: 2-(4-methoxy-2-methylanilino)-2-oxazoline2-(2,3,4-trichloroanilino)-2-oxazoline 2-(2,3-dichloro-1-indanylamino)-2-oxazoline 5-methyl-2-(2,3-dimethylanilino)-2-oxazoline 2-(2-bromo-1-indanylamino)-4-methyl-2-oxazoline 4-ethyl-2-(2,3-dimethylanilino)-2-oxazoline 2-(4-ethyl-1-indanylamino)-1,5-dimethyl-2-oxazoline 4,4-dimethyl-2-(2-methyl-3-chloroanilino)-2-oxazoline 2-(2,3,5-triiodo-1-indanylamino)-2-oxazoline 5-butyl-2-(2-methylanilino)-2-oxazoline 2-(3,4-bismethylthio-l-indanylamino)-4-butyl-2-oxazoline 2-(2-dimethylaminoanilino)-2-oxazoline 2-(2,3,5-tri-sec-butoxy-i-indanylamino)-4,5-diethyl-2-ox 2-(3-methylthioanilino)-2-oxazoline azoline 2-(2-trifluoromethylanilino)-2-oxazoline 2-(4-tert-butylthio-l-indanylamino)-2-oxazoline O 2-(2,3,5-trimethyl-1-indanylamino)-2-oxazoline 2-(2-trifluoromethoxy-3-methylanilino)-2-oxazoline 2-(2,3,5-trimethylthio-l-indanylamino)-2-oxazoline 2-(2,4,5-trimethylanilino)-2-oxazoline 2-(2,7-diethoxy-1-indanylamino)-4,5-dimethyl-2-oxazoline 4-methyl-2-(2-methyl-5-isopropylanilino)-2-oxazoline 2-(4-isopropylthio-1-indanylamino)-5-ethyl-2-oxazoline 2-(2,5-dimethoxyanilino)-2-oxazoline Illustrative of the compounds within the scope of Formula 15 5-methyl-2-(2,4-dimethoxy-5-chloroanilino)-2-oxazoline (4) above are the following: 2-(2-fluoroanilino)-2-oxazoline 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline 2-(2-bromo-4-methylanilino)-2-oxazoline 2-(5,6,7,8-tetrahydro-2-chloro-1-naphthylamino)-2-ox 2-(2,5-diethoxyanilino)-2-oxazoline azoline 2-(3-chloro-4-methylanilino)-2-oxazoline 2-(5,6,7,8-tetrahydro-3,4-dimethyl-1-naphthylamino)-2- 20 2-(2,6-diethylanilino)-2-oxazoline oxazoline 2-(4-chloro-2-trifluoromethylanilino)-2-oxazoline 2-(5,6,7,8-tetrahydro-1-naphthylamino)-4-butyl-2-ox 2-(3-chloro-4-fluoroanilino)-2-oxazoline azoline 2-(4-fluoro-2-methylanilino)-2-oxazoline 2-(5,6,7,8-tetrahydro-2-methyl-1-naphthylamino)-2-ox In the practice of the present invention it should be fully ap azoline 25 preciated that administration of the anticholinergic and the 2-(5,6,7,8-tetrahydro-4-chloro-1-naphthylamino)-2-ox arylaminooxazoline for the intended profound depressant ef azoline fect will be more or less concurrent, i.e., united in action, and 2-(5,6,7,8-tetrahydro-2,4-diiodo-1-naphthylamino)-2-ox not necessarily simultaneously, i.e., in the same pharmaceuti azoline cal formulation or dosage unit. Thus, it will be understood that 2-(5,6,7,8-tetrahydro-2,5-dibromo-l-naphthylamino)-4- 30 the synergistic benefits of the present invention will be readily butyl-2-oxazoline obtainable even though either one or the other of the two es sential materials may be administered somewhat prior to or 2-(5,6,7,8-tetrahydro-2,3,4-trimethylthio-1-naphthyl subsequent to the administration of the other. For example, 2-(5,6,7,8-tetrahydro-4-fluoro-1-naphthylamino)-4,5-amino)-2-oxazoline for gradual inducement of profound central nervous system dimethyl-2-oxazoline 35 depression with apparent unconsciousness in a patient, it may 2-(5,6,7,8-tetrahydro-2,4-diethyl-1-naphthylamino)-2-ox under some circumstances be desirable to administer first the azoline arylaminooxazoline, perhaps orally, followed within say 30 2-(5,6,7,8-tetrahydro-2,3-dimethoxy-1-naphthylamino)-4- minutes or an hour by administration, perhaps by injection, of methyl-2-oxazoline the synergistic amount of the anticholinergic agent. 40 Of course the precise length of time which can elapse 2-(5,6,7,8-tetrahydro-2,3,5-tri-sec-butoxy-1-naphthyl between administration of the anticholinergic and the amino)-2-oxazoline arylaminooxazoline, or vice versa, to still obtain the syner 2-(5,6,7,8-tetrahydro-2,5-dimethylthio-1-naphthylamino)- gistic co-action of the compounds has not been determined for 4-methyl-5-sec-butyl-2-oxazoline each combination of the two different materials possible ac 2-(5,6,7,8-tetrahydro-2,5-bisethylthio-1-naphthyl-amino)- 45 cording to this invention. The precise time lapse will depend 4,5-dimethyl-2-oxazoline on the amount of each administered, the condition of the 2-(5,6,7,8-tetrahydro-2,3-diethoxy-i-naphthylamino)-2-ox recipient, the absorption characteristics of each material, the azoline dosage form or method, the nature of the effect desired, etc., 2-(5,6,7,8-tetrahydro-3,4-dichloro-1-naphthylamino)-2-ox as will be determined by the attendant physician or veterinari azoline 50 an. Generally speaking, it is believed that provided the 2-(5,6,7,8-tetrahydro-3-bromo-1-naphthylamino)-4- dosages of each are sufficient, the synergistic action is ob methyl-2-oxazoline tainable if the two components are administered within, say, 2 2-(5,6,7,8-tetrahydro-3,4,5-triiodo-1-naphthylamino)-4,5- or 3 hours of each other. dimethyl-2-oxazoline The amount of each of the two essential materials to be ad 2-(5,6,7,8-tetrahydro-4-isopropyl-1-naphthylamino)-2-ox 55 ministered will of course also depend upon the variables just azoline mentioned but, in general, the arylamino-oxazoline will be ad 2-(5,6,7,8-tetrahydro-4-trifluoromethyl-1-naphthylamino)- ministered in the range of about 0.1 to 500 milligrams per day. 2-oxazoline For the synergistic effect, for each part by weight of 2-(5,6,7,8-tetrahydro-4-trifluoromethoxy-1- arylaminooxazoline used, there will usually be used from naphthylamino)-2oxazoline 60 about 0.5 to about 30 parts by weight of anticholinergic agent, Illustrative of the compounds within the scope of Formula and preferably about 0.5 to about 5 parts by weight of the (5) above are the following: latter. The absolute potency of each of the ingredients will of 2-(4-indanylamino)-2-oxazoline course be the prime determining factors, 2-(2-chloro-4-indanylamino)-2-oxazoline As mentioned above, in general, the physician or veterinari 2-(2,5-diiodo-4-indanylamino)-2-oxazoline 65 an will, of course, determine the dosage of each and the total 2-(3,5-bis-propylthio-4-indanylamino)-2-oxazoline dosage which will be most suitable for a particular application, 2-(2-methyl-4-indanylamino)-2-oxazoline and as might be expected, it will vary with the age, weight and Illustrative of the compounds within the scope of Formula general health of the patient under treatment and with various (6) are the following: other factors which will be determined by the physician or 2-(2-toluidino)-2-oxazoline 70 2-(2,3-dimethylanilino)-2-oxazoline veterinarian in attendance. When they are administered orally 2-(3-chloro-2-methylanilino)-2-oxazoline a larger quantity will be required to produce the same effect as 2-(2-ethylanilino)-2-oxazoline a smaller quantity given parenterally. Parenteral administra 2-(3,4-dimethylanilino)-2-oxazoline tion of from 0.1 mg. to 250 mg. of each active agent should be suitable to obtain some effect. Administration can also be by 2-(3-isopropylanilino)-2-oxazoline 75 vapor or spray through the mouth or nasal passages. 3,679,798 7 8 In animal tests to date no synergism of cardiovascular ac by a conventional tableting machine, Slow release pills and tions has thus far been noted. Furthermore, based on tests to tablets can also be used. date, it is believed that the surprising synergism in inducement of profound central nervous system depression obtained ac EXAMPLE 4 cording to the present invention is achieved without at the 5 same time substantially altering the normally expected effect A parenteral composition suitable for administration by in of centrally acting anticholinergic agents on the heart rate. jection is prepared by dissolving 5 percent by weight of the ac In the practice of this invention, the active pharmaceutical tive ingredients of Example in 95 percent by volume of agents may be administered alone but are generally ad physiological saline and sterilizing the resultant solution by fil ministered with a pharmaceutical carrier selected on the basis O tration. A buffer can be used if desired. of the chosen route of administration and standard phar maceutical practice. For example, they may be administered EXAMPLE5 orally in the form of tablets or capsules containing such ex 2-(5,6,7,8-tetrahydro- 1-naphthylamino )-2-oxazoline (0.2 cipients as starch, milk sugar, certain types of clay, etc. They 15 may be administered orally in the form of elixirs or oral parts by weight) is dissolved at a concentration of 2 milligrams suspensions which may contain coloring and flavoring agents. per milliliter in a mixture of 25 parts by weight of polyethylene They may be injected parenterally and for this use may be glycol ("Carbowax' 400) and 75 parts by weight of physiolog prepared in the form of sterile aqueous solutions containing ical saline. The resulting solution is then combined with an other solutes such as saline or glucose in sufficiefit quantity to 20 equal volume of a solution of 4 milligrams of atropine sulfate make the solution isotonic. For intramuscular administration dissolved in 1 milliliter of physiological saline. The combined compositions of the compounds of this invention may be solution is injected into the cephalic vein of a 2-year old bea prepared in an oil base such as peanut or sesame oil. gle dog so that a total of 0.1 milligram of the oxazoline and 0.2 Compositions useful in the practice of the present invention milligram of the atropine sulfate, per kilogram of body weight may take a variety of forms. Various diluents may be em of the dog, is administered. In about 15 minutes the animal ployed and the percentage of active ingredients may be varied. becomes depressed and passes into a state of deep central ner It is necessary that the active ingredient or ingredients form a vous system depression in which the animal does not respond proportion of the composition such that a suitable dosage to painful stimuli. This state lasts for about 1 to 2 hours follow form will be obtained. Obviously several dosage unit forms 30 ing which the animal recovers normal functions with no can be administered at about the same time. Although com deleterious after-effects. positions with less than 0.005 percent by weight of either ac tive ingredient are Suitable, it is preferred to use compositions EXAMPLE 6 containing not less than 0.005 percent of either active agent because otherwise the amount of carrier becomes excessively 35 A 1-year old female dog is given an intravenous injection of large. Activity normally increases with the concentration of atropine sulfate dissolved in 0.4 percent by weight concentra the active agent. The percentage by weight of single or con tion in physiological saline. The injection is sufficient to in bined active agents can be 10, 50, 75, 95 percent or even troduce 0.2 milligram of the atropine sulfate per kilogram of higher. Dosage unit forms may be prepared with a minor pro body weight of the dog. The injection of atropine sulfate is fol portion of a carrier and a major proportion of active materials 40 lowed 10 minutes later by intravenous injection of 2-(5,6,7,8- and vice versa. tetrahydro-1-naphthylamino)-2-oxazoline, dissolved in 0.2 The following examples are given solely for the purpose of percent by weight concentration in polyethylene glycol (25 illustration and are not to be construed as limitations of this in parts) and physiological saline (75 parts), in amount sufficient vention, many variations of which are possible without depart- 45 to introduce 0.1 milligram of the oxazoline per kilogram of ing from the spirit or scope thereof. body weight. In about 15 minutes the animal becomes depressed and passes into a state of deep central nervous EXAMPLE 1. system depression in which the animal does not respond to A large number of unit capsules are prepared for oral ad painful stimuli. This state lasts for about 1 to 2 hours following ministration by mixing the following ingredients: 50 which the animal recovers normal functions with no deleteri ous after-effects. Parts by Weight 2-(5,6,7,8-tetrahydro-1-naphthyl EXAMPLE 7 amino)-2-oxazoline 650 scopolamine hydrobromide 1,300 55 2-(2,3-dimethylanilino)-2-oxazoline (3 parts by weight) is lactose U.S.P. 8,000 Dry pyrogenic silica SiO, with 50 dissolved in 1,000 parts by weight of a mixture of 25 parts by particle size of 0.015 microns, weight of polyethylene glycol (“Carbowax' 400) and 75 parts surface area of 200 m/gm, and bulk by weight of physiological saline. The resulting solution is in density of 2.2 lbs/cu. ft. jected intravenously into a 2-year old male dog in an amount (''Cabosil," Cabot Corp.) 60 to introduce 0.132 milligram of oxazoline per kilogram of After mixing, the mixture is screed through a 40 mesh screen body weight of the dog. This injection is followed in 10 and encapsulated in No. 3 two-piece hard gelatin capsules. minutes by intravenous administration of a normal saline solu tion of atropine sulfate, sufficient to introduce 0.5 milligram EXAMPLE 2 65 of atropine sulfate per kilogram of body weight of the dog. In The active ingredients of Example 1 (20 parts by weight) is about 15 minutes the animal becomes depressed and passes dispersed in 100 parts by volume of corn oil and encapsulated into a state of deep central nervous system depression in in standard soft gelatin capsules. which the animal does not respond to painful stimuli. This state lasts for about 1 to 2 hours following which the animal EXAMPLE 3 70 recovers normal functions with no deleterious after-effects. Tablets for oral administration are prepared by mixing 50 EXAMPLE 8 milligrams of the active ingredients of Example 1, 2.5 milli Example 7 is repeated, except that scopolamine hydrobro grams of gelatin, 2.5 milligrams of magnesium stearate and mide is used in place of the atropine sulfate, with similar 100 milligrams of starch, and forming the mixture into tablets 75 results. 3,679,798 9 10 EXAMPLE 9 Example 6 is repeated, except that in place of the atropine " (--- ) o--R sulfate there is used an amount of phenyl cyclopentylglycolic -NH-C acid, N-ethylpiperidinolester, sufficient to introduce 0.2 milli- 5 N- -R2 gram of the ester per kilogram of body weight of the dog, with 3. similar results. R EXAMPLE 10 (4)4. 4 R Example 5 is repeated, except that in place of the atropine 10 --- -NH-c? O-C-R1 there is used an amount of benzilic acid, beta- S diethylaminoethyl ester, sufficient to introduce 0.1 milligram N- -R2 of the ester per kilogram of body weight of the dog, with R3 similar results. (5) R 15 l EXAMPLE 11 -o- -R1 Rhesus monkeys are exposed for 5 minutes in a dynamic -NH-c l chamber to an atmosphere containing 400 micrograms per N--R liter of 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline 20 R3 and 800 micrograms per liter of scopolamine aspirated into and the chamber in the form of an aerosol. Within 3 to 5 minutes (6) R the animals become prostrate, severely depressed and ap- A. o-c-R parently unconscious for a period of about 1 hour. NH c^ EXAMPLES 12 - 26 25 B N-di-Ra The procedures of Examples 5 and 6 are repeated except k that the following listed anticholinergic agents and where in each of Formulas (1) through (6) R,R,R, and R' arylaminooxazolines are substituted in like amount by weight are each separately selected from the group consisting of for those of Examples 5 and 6 respectively. They are ad- 30 hydrogen and alkyl of one through four carbons with the ministered in like manner and provide like results. total number of carbons in these four substituents being Amount Amount (mg.jkg.) 2-oxazolinic (mg/kg.) Allticholinergic Example: 12.------0.25 2-(1-naphthylamino)------0. 500 Atropille sulfate. 0.2 2-(4-methoxy-l-liphthylamino)- 0.400 Scopolamine hydrobronhide. 0.2 - - - - -do------5.00 Belzety zine. 0.2 2-(2-methyl-1-naphthylamino)-- - - 0.400 Scopolamine hydrobromide. 1.0 2-(4-Inethyl-1-naphtlylamino)------... 1.00 Atropine sulfate. 0. 25,lillaO)-. stetrahydro-1-naphthyl- 10, 00 Tresentine. 0.1 2-(4-methyl-5,6,7,8-tetrahydro-1-napll- 0. 500 Benztropine. thylamino)-. 0. 5 2-(4-methoxy-5,6,7,8-tetrahydro-1-naphthylamino)-. 1, 00 Ditran. 0.1 2-tetrahydro-1-naphthyl-all IO)- 25.00 Caramiphen.

0.25 2-(2-methylanilino)------. . 0. 500 Cyclopentolate. ().5 2-(2-ethylanilino)------5.00 Cycrimine hydrochloride. 0. 1 2-(2,3-dimethylamilino)------50.0 Ethopropazine. 0.25 2-(2-chloro-2-methylanilino)------. 50.0 IPiparidolate. 0, i. 2-(2,6-dimethylanilino)------20. (). Oxyphencyclimine. 0.75 2-(4-methoxy-2-methylaanilino)------5.00 Tricyclanhol. The invention claimed is: 50 8; where in each of Formulas (1) through (5), one 1. The method comprising administering to a warm-blooded through three hydrogen atoms of the moiety selected animal two essential substances within 3 hours of each other, from the group consisting of naphthyl, partially reduced the first essential substance being a centrally acting an- naphthyl and indanyl can be replaced with a member ticholinergic agent and the second essential substance being selected from the group consisting of halogen, alkyl of selected from the group consisting of a 2-arylamino-2-ox- 55 one through four carbons, alkoxy of one through four car azoline and pharmaceutically acceptable acid addition salts bons, alkylthio of one through four carbons, thereof, there being used from about 0.5 to 30 parts by weight trifluoromethyl and trifluoromethoxy; and of said anticholinergic agent for each part by weight of said where in Formula (6) A is selected from the group consist second essential substance, and said 2-arylamino-2-oxazoline ing of hydrogen, alkyl of one through four carbons, alkox being a compound selected from the group consisting of 60 y of one through four carbons and halogen; B is selected from the group consisting of alkyl of one (1) R through four carbons, alkoxy of one through four carbons d and halogen; and -a- o- -R C is selected from the group consisting of hydrogen, alkyl of -NH-C 65 one through four carbons, alkoxy of one through four car N-d–R: bons, halogen, alkylthio of one through four carbons, al k koxyalkyl wherein the alkoxy portion has one through two carbons and the alkyl portion has one through two (2 R carbons, alkylamino of one through two carbons, dial o-é-R 70 kylamino where each alkyl group has one through two / carbons, trifluoromethyl and trifluoromethoxy. -NH-c. 2. The method according to claim 1 where said centrally N-C-R acting anticholinergic is a glycolate. k 3. The method comprising administering to a warm-blooded 75 animal, within an hour of each other, a compound selected 3,679,798 from the group consisting of 2-(1 -naphthylamino)-2-ox azoline and pharmaceutically acceptable acid addition salts of said oxazoline and, for each one part by weight of said com pound, from about 0.5 to 30 parts by weight of a centrally act ing anticholinergic agent, said oxazoline having the formula R where R, R, R, and Rare each selected from the group con o--R sisting of hydrogen and alkyl of one through four carbons with { -NH-C N the total number of carbons in each of these four substituents N- -R O being eight; and where one through three of the hydrogen R atoms in the partially reduced naphthyl group can be replaced where R, R, R, and Rare each selected from the group con consisting of halogen, alkyl of one through four carbons, al sisting of hydrogen and alkyl of one through four carbons with koxy of one through four carbons, alkylthio of one through the total number of carbons in each of these four substituents 15 four carbons, trifluoromethyl and trifluoromethoxy. being eight; and where one through three of the hydrogen 7. The method comprising administering to a warm-blooded atoms in the naphthyl group can be replaced with a member animal, within an hour of each other, a compound selected selected from the group consisting of halogen, alkyl of one from the group consisting of a 2-(4-indanylamino)-2-ox through four carbons, alkoxy of one through four carbons, al azoline and pharmaceutically acceptable acid addition salts of kylthio of one through four carbons, trifluoromethyl and 20 said oxazoline and, for each one part by weight of said com trifluoromethoxy. pound, from about 0.5 to 30 parts by weight of a centrally act 4. The method comprising administering to a warm-blooded ing anticholinergic agent, said oxazoline having the formula animal, within a hour of each other, a compound selected R from the group consisting of a 2-(1,2,3,4-tetrahydro-1- o-c-R naphthylamino)-2-oxazoline and pharmaceutically acceptable 25 / acid addition salts of said oxazoline and, for each one part by weight of said compound, from about 0.5 to 30 parts by weight 5. of a centrally acting anticholinergic agent, said oxazoline hav h: ing the formula 30 where R, R', R', and Rare each selected from the group con R sisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen atoms in the indanyl group can be replaced with a member selected from the group consisting of halogen, alkyl of one 35 through four carbons, alkoxy of one through four carbons, al R2 kylthio of one through four carbons, trifluoromethyl and where R, R, R and Rare each selected from the group con trifluoromethoxy. sisting of hydrogen and alkyl of one through four carbons with 8. The method comprising administering to a warm-blooded the total number of carbons in each of these four substituents animal, within an hour of each other, a compound selected being eight; and where one through three of the hydrogen 40 from the group consisting of a 2-anilino-2-oxazoline and phar atoms in the partially reduced naphthyl group can be replaced maceutically acceptable acid addition salts of said oxazoline with a member selected from the group consisting of halogen, and, for each one part by weight of said compound, from alkyl of one through four carbons, alkoxy of one through four about 0.5 to 30 parts by weight of a centrally acting an carbons, alkylthio of one through four carbons, ticholinergic agent, said oxazoline having the formula trifluoromethyl and trifluoromethoxy. 45 R 5. The method comprising administering to a warm-blooded A. o-c-R animal, within an hour of each other, a compound selected from the group consisting of a 2-(1-indanyl)-2-oxazoline and -NH-cC l - pharmaceuticafly acceptable acid addition salts of said ox B N-C-R azoline and, for each one part by weight of said compound, 50 k from about 0.5 to 30 parts by weight of a centrally acting an where R,R,R, and Rare each selected from the group con ticholinergic agent, said oxazoline having the formula sisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents 55 being eight, A is selected from the group consisting of hydrogen, alkyl of one through four carbons, alkoxy of one through four carbons and halogen; B is selected from the group consisting of alkyl of one through four carbons, alkoxy of one through four carbons and halogen; and C is selected 60 from the group consisting of hydrogen, alkyl of one through where R,R,R, and Rare each selected from the group con four carbons, alkoxy of one through four carbons, halogen, sisting of hydrogen and alkyl of one through four carbons with alkyl-thio of one through four carbons, alkoxyalkyl wherein the total number of carbons in each of these four substituents the alkoxy portion has one through two carbons and the alkyl being eight; and where one through three of the hydrogen portion has one through two carbons, alkylamino of one atoms in the indanyl group can be replaced with a member 65 through two carbons, dialkylamino where each alkyl group selected from the group consisting of halogen, alkyl of one has one through two carbons, trifluoromethyl and through four carbons, alkoxy of one through four carbons, al trifluoromethoxy. - kylthio of one through four carbons, trifluoromethyl and 9. The method according to claim 1 wherein said an trifluoromethoxy. ticholinergic agent is atropine sulfate and said oxazoline is 2 6. The method comprising administering to a warm-blooded 70 (5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline. animal, within an hour of each other, a compound selected 10. The method according to claim 1 wherein said an from the group consisting of a 2-(5,6,7,8-tetrahydro-1- ticholinergic agent is atropine sulfate and said oxazoline is 2 naphthylamino)-2-oxazoline and pharmaceutically acceptable (2,3-dimethylanilino)-2-oxazoline. acid addition salts of said oxazoline and, for each one part by 11. The method according to claim 1 wherein said an weight of said compound, from about 0.5 to 30 parts by weight 75 ticholinergic agent is scopolamine hydrobromide and said ox of a centrally acting anticholinergic agent, said oxazoline hav azoline is 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-ox ing the formula: azoline. 3,679,798 13 4. 12. The method according to claim 1 wherein said an selected from the group consisting of halogen, alkyl of ticholinergic agent is scopolamine hydrobromide and said ox one through four carbons, alkoxy of one through four car azoline is 2-(2,3-dimethylanilino)-2-oxazoline. bons, alkylthio of one through four carbons, 13. The method according to claim 1 wherein said an trifluoromethyl and trifluoromethoxy; and where in For ticholinergic agent is benzilic acid, phenyl cyclopentylglycolic mula (6) A is selected from the group consisting of acid, N-ethylpiperidinol ester, and said oxazoline is 2-(5,6,7,8- hydrogen, alkyl of one through four carbons, alkoxy of tetrahydro-1-naphthylamino)-2-oxazoline. one through four carbons and halogen; 14. The method according to claim 1 wherein said an B is selected from the group consisting of alkyl of one ticholinergic agent is benzilic acid, phenyl cyclopentylglycolic through four carbons, alkoxy of one through four carbons acid, N-ethylpiperidinol ester, and said oxazoline is 2-(2,3- O and halogen; and dimethylanilino)-2-oxazoline. C is selected from the group consisting of hydrogen, alkyl of 15. The method according to claim 1 wherein said an one through four carbons, alkoxy of one through four car ticholinergic agent is benzilic acid, beta-diethylaminoethyl bons halogen, alkylthio of one through four carbons, al ester, and said oxazoline is 2-(5,6,7,8-tetrahydro-1- koxyalkyl wherein the alkoxy portion has one through naphthylamino)-2-oxazoline. 15 two carbons and the alkyl portion has one through two 16. The method according to claim 1 wherein said an carbons, alkylamino of one through two carbons, dial ticholinergic agent is benzilic acid, beta-diethylaminoethyl kylamino where each alkyl group has one through two ester, and said oxazoline is 2-(2,3-dimethyl-anilino)-2-ox carbons, trifluoromethyl and trifluoromethoxy. azoline. 18. A composition according to claim 17 wherein said cen 17. A composition comprising one part by weight of an 20 trally acting anticholinergic is a glycolate. arylaminooxazoline and from about 0.5 to 30 parts by weight 19. A composition comprising one part by weight of an of a centrally acting anticholinergic agent, said arylaminoox arylaminooxazoline and from about 0.5 to 30 parts by weight azoline being selected from the group consisting of those of of a centrally acting anticholinergic agent, said arylaminoox the following formulas and pharmaceutically acceptable acid azoline being selected from the group consisting of those of addition salts thereof. 25 the following formula and pharmaceutically acceptable acid (1) R addition salts thereof. Ctle 30 le R3 (2) R where R, R', R, and Rare each selected from the group con 35 sisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents being eight; and where one through three of the hydrogen tle atoms in the naphthyl group can be replaced with a member R3 selected from the group consisting of halogen, alkyl of one 40 through four carbons, alkoxy of one through four carbons, al (3) R kylthio of one through four carbons, trifluoromethyl and trifluoromethoxy. 20. A composition comprising one part by weight of an NH-CS arylaminooxazoline and from about 0.5 to 30 parts by weight N-C-R2 45 of a centrally acting anticholinergic agent, said arylaminoox 3 azoline being selected from the group consisting of those of the following formula and pharmaceutically acceptable acid (4) {D addition salts thereof: g --- X-NH-C 50 3. o-di-R le -Nite,N-d-R: (5) O-C-R1 55 where R, R, R', and Rare each selected from the group con sisting of hydrogen and alkyl of one through four carbons with the total number of carbons in each of these four substituents { X-NH-cCSN--Rs being eight; and where one through three of the hydrogen X k atoms in the partially reduced naphthyl group can be replaced and 60 with a member selected from the group consisting of halogen, alkyl of one through four carbons, alkoxy of one through four (6) R carbons, alkylthio of one through four carbons, A. o-c-R trifluoromethyl and trifluoromethoxy. NH-c? 21. A composition comprisinG one part by weight of an 65 arylaminooxazoline and from about 0.5 to 30 parts by weight of a centrally acting anticholinergic agent, said arylaminoox R3 azoline being selected from the group consisting of those of where in each of Formulas (1) through (6) R, R, R, and R' the following formula and pharmaceutically acceptable acid are each separately selected from the group consisting of addition salts thereof: hydrogen and alkyl of one through four carbons with the 70 total number of carbons in these four substituents being I eight; where in each of Formulas (1) through (5), 1 { D through 3 hydrogen atoms of the moiety selected from the group consisting of naphthyl, partially reduced | > C I. 75 naphthyl and indanyl can be replaced with a member R 3,679,798 6 where R,R,R, and Rare each selected from the group con azoline being selected from the group consisting of those of sisting of hydrogen and alkyl of one through four carbons with the following formula and pharmaceutically acceptable acid the total number of carbons in each of these four substituents addition salts thereof: being eight; and where one through three of the hydrogen atoms in the indanyl group can be replaced with a member R selected from the group consisting of halogen, alkyl of one A. o--R through four carbons, alkoxy of one through four carbons, al -NH-C kylthio of one through four carbons, trifluoromethyl and N trifluoromethoxy. B N-C-R2 22. A composition comprising one part by weight of an O k arylaminooxazoline and from about 0.5 to 30 parts by weight where R,R,R, and Rare each selected from the group con of a centrally acting anticholinergic agent, said arylaminoox sisting of hydrogen and alkyl of one through four carbons with azoline being selected from the group consisting of those of the total number of carbons in each of these four substituents the following formula and pharmaceutically acceptable acid being eight; A is selected from the group consisting of addition salts thereof , 15 hydrogen, alkyl of one through four carbons, alkoxy of one through four carbons and halogen; B is selected from the group consisting of alkyl of one through four carbons, alkoxy of one through four carbons and halogen; and C is selected from the group consisting of hydrogen, alkyl of one through 20 four carbons, alkoxy of one through four carbons, halogen, al kylthio of one through four carbons, alkoxyalkyl wherein the R3 alkoxy portion has one through two carbons and the alkyl por where R. R', R, and R' are each selected from the group tion has one through two carbons, alkylamino of one through consisting of hydrogen and alkyl of one through four carbons two carbons, dialkylamino where each alkyl group has one with the total number of carbons in each of these four sub 25 through two carbons, trifluoromethyl and trifluoromethoxy. stituents being eight; and where one through three of the 25. A composition comprising by weight 1 part of 2 hydrogen atoms in the partially reduced naphthyl group can (5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline and 0.5-30 be replaced consisting of halogen, alkyl of one through four parts of atropine sulfate. carbons, alkoxy of one through four carbons, alkylthio of one 26. A composition comprising by weight 1 part of 2-(2,3- through four carbons, trifluoromethyl and trifluoromethoxy. 30 dimethylanilino)-2-oxazoline and 0.5-30 parts of atropine 23. A composition comprising one part by weight of an sulfate. arylaminooxazoline and from about 0.5 to 30 parts by weight 27. A composition comprising by weight 1 part of 2 of a centrally acting anticholinergic agent, said arylaminoox (5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline and 0.5 to azoline being selected from the group consisting of those of 30 parts of scopolamine hydrobromide. the following formula and pharmaceutically acceptable acid 35 28. A composition comprising by weight 1 part of 2-(2,3- addition salts thereof dimethylanilino)-2-oxazoline and 0.5-30 parts of scopolamine hydrobromide. 29. A composition comprising by weight part of 2 (5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline and 0.5 to -N-C 40 30 parts of benzilic acid, phenyl cyclopentylglycolic acid, N 6.N-C-R2 ethylpiperidinolester. 30. A composition comprising by weight 1 part of 2-(2,3- dimethylanilino)-2-oxazoline and 0.5 to 30 parts of benzilic where R, R', R', and R are each selected from the group acid, phenyl cyclopentylglycolic acid, N-ethylpiperidinol consisting of hydrogen and alkyl of one through four carbons 45 ester. with the total number of carbons in each of these four sub 31. A composition comprising by weight part of 2-(2,3- stituents being eight; and where one through three of the dimethylanilino)-2-oxazoline 0.5 to 30 parts of benzilic acid, hydrogen atoms in the indanyl group can be replaced with a phenyl cyclopentylglycolic acid, N-ethylpiperidinolester. member selected from the group consisting of halogen, alkyl 31. A composition comprising by weight 1 part of 2 of one through four carbons, alkoxy of one through four car 50 (5,6,7,8-tetrahydro-1-naphthylamino)-2-oxazoline and 0.5 to bons, alkylthio of one through four carbons, trifluoromethyl 30 parts of benzilic acid, beta-diethylaminoethyl ester. and trifluoromethoxy. 32. A composition comprising by weight 1 part of 2-(2,3- 24. A composition comprising one part by weight of an dimethylanilino)-2-oxazoline and 0.5-30 parts of benzilic arylaminooxazoline and from about 0.5 to 30 parts by weight acid, beta-diethylaminoethyl ester. of a centrally acting anticholinergic agent, said arylaminoox 55 sk :k sk k k

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