3,636,219 United States Patent Office Patented Jan. 18, 1972

1. 2 benactyzine, also identified as beta-diethylaminoethyl 3,636,219 benzilate ANTICHOLINERGIC COMPOSITIONS CONTAIN. NG CERTAIN THIAZOLINES OR MEDAZOLNES benztropine, also identified as 3-diphenylmethoxytropane Rudolf Culik, Kennett Square, Pa., and Jurg A. Schneider, caramiphen, also identified as 1-phenylcyclopentanecar Wilmington, Del, assignors to E. I. du Pont de boxylic acid, diethylaminoethyl ester Nemours and Company, Wilmington, Del. cyclopentolate, also identified as 1-hydroxy-alphaphenyl No Drawing. Filed Mar. 2, 1964, Ser. No. 348,884 cyclopentaneacetic acid, 2-dimethylaminoethyl ester Int. C. A61k 27/00 cycrimine, also identified as alpha-cyclopentylalpha-phen U.S. C. 424-265 48 Claims yl-1-piperidinepropanol This invention relates to pharmaceutical compositions 0 ditran, also identified as N-ethyl-3-piperidyl phenyl cyclo useful for both human and veterinary applications. More pentyl glycolate particularly, this invention relates to synergistic utiliza ethopropazine, also identified as 10-(2-diethylaminopro tion of one or more centrally acting anticholinergic Sub pyl)phenothiazine stances and one or more of a class of central nervous Sys oxyphencyclimine, also identified as 1-methyl-1,4,5,6-te tem depressants. trahydro - 2 - pyrimidylmethyl alpha-cyclohexylalpha The disclosure herein should not be taken as a recom phenylglycolate mendation to use the disclosed invention in any Way piperidolate, also identified as N-ethyl-3-piperidyl diphen without full compliance with U.S. Food and Drug laws ylacetate and other laws and governmental regulations which may systral, also identified as chlorphenoxamine and beta-di be applicable. 20 methylaminoethyl (p-chloro-alpha-methylbenzhydryl) According to the present invention, an amazing Syner ether gism has been noted between a centrally acting anticholi tricyclamol, also identified as procyclidine and alpha-cy nergic and compounds in a class generically identified as clohexyl-alpha-phenyl-1-pyrrolidinepropanol 2-arylamino-2-thiazolines and 2-arylamino-2-imidazolines. trihexyphenidyl, also identified as alpha-cyclohexyl-alpha While the thiazolines and imidazolines themselves have phenyl-1-piperidinepropanol activity, some to a remarkable extent, as regulators and in particular depressant of the central nervous system, we In addition to the above-mentioned anticholinergics, have now discovered that, when used with a centrally act other illustrative materials include homatorpine, atroscine, ing anticholinergic, the synergistic combination according eucatropine, syntropan (amprotropine), pavatrine, ban to this invention effects a profound action, producing a 30 thine (methantheline), pro-banthine (propantheline), striking depression of central nervous system control of oxypenonium (antrenyl) penthienate (monodral), di skeletal muscle as well as a striking loss of responses to phenmethanil (prantal), mepiperphenidol (darstine), di painful stimuli. This effect resembles a deep surgical cyclomine (bentyl), aminopentamide (centrine), dibuto anesthesia, producing unconsciousness in the recipient in line and the like. a very short time. As will be readily understood, the centrally acting anti Centrally acting anticholinergics are a well-recognized cholinergics will most often be used in the form of an class of pharmacologically active substances. As is well acid addition salt with an acid having a pharmaceutically known and understood by pharmacologists, these anti aceptable anion. The term "pharmaceutically acceptable cholinergics can be naturally occurring or synthetic and anion” has a definite meaning to one skilled in the art, are those substances which act to inhibit and have a high 40 namely, a non-toxic anion of any of the simple acids com ly selective blocking action on effector organs innervated mercially used to neutralize basic medicinal agents. These by postganglionic cholinergic nerves. As is known to per acids include, for example, hydrochloric, hydrobromic, sons skilled in this art, anticholinergic agents containing a hydriodic, sulfuric, succinic, maleic, tartaric, citric, gly quaternary nitrogen moiety are of course not centrally act colic, and others. The pharmaceutical activity of the mole 1ng. 45 cule is primarily but not necessarily exclusively a function Perhaps the best known centrally acting anticholinergics of the cation. are the natural occurring alkaloids of the belladonna By way of further illustration of the salts of anti plants. The two most important of these alkaloids are cholinergic agents, it can be mentioned that atropine is atropine (d1-hyoscyamine) and scopolamine (1-hyoscine) preferably used as the hydrobromide, hydrochloride, meth and these two materials are the preferred Synergists ac 50 ylbromide, methylnitrate, salicylate, sulfate, atropine cording to the present invention because of their signifi sulfuric acid, valerate, aurichloride, platinichloride, oxa cantly outstanding synergizing action with the 2-aryl late or picrate; scopolamine as the hydrobromide, hydro amino-2-thiazolines and the 2-arylamino-2-imidazolines. chloride, aurichloride, auribromide, picrate, methylbro Also of special importance because of outstanding activity mide, methylnitrate or aminoxide; Adephenine (registered are the centrally acting anticholinergic glycolates. 5 5 trademark) as the hydrochloride; benactyzine as the hy However, the use of all centrally acting anticholinergic drochloride; benztropine as the methanesulfonate; carami substances is intended to be embraced within the concept phen as the hydrochloride or ethanedisulfonate; cycri of the present invention. Illustrative of Such anticholiner mine as the hydrochloride; oxyphencyclimine as the hy gics are the following: drochloride; systral as the hydrochloride; and trihexy Adephenine (registered trademark), also identified as Tra 60 phenidyl as the hydrochloride. sentine (registered trademark) and 2-diethylamino The second essential ingredient of the synergistic com ethyl diphenylacetate positions of the present invention is a 2-arylamino-2- 3,636,219 3 4. thiazoline or a 2-arylamino-2-imidazoline having central carbons, alkylamino of 1 or 2 carbons, dialkylamino nervous system depressant activity. Suitable 2-arylamino where the alkyl group can be the same or different and thiazolines or 2-arylamino-2-imidazolines include those each has 1 or 2 carbons, trifluoromethyl or trifluoro of the following formulas: methoxy. PREPARATION (1) The thiazoline compounds used in this invention are made in the manner described for the thiazoline com -N H-C pounds of U.S. Pat. 2,027,030. Appropriate substitution 8 -R2 0 of starting materials such as naphthyl-isothio-cyanates SkX and indanyl-isothio-cyanates for the phenyl-isothiocya nates will produce the desired compounds. The imidazoline compounds used in this invention are (2) made in the manner described for the imidazolines of U.S. Pat. 2,899,426. Appropriate substitution of starting 5 materials as will be known to an expert in the art produces the desired compounds. Generally, the compounds used in this invention are crystalline solids. They can be readily prepared by re action of the appropriately selected arylamine and an appropriate alkyl thiocyanate to form the corresponding (3) N-aryl-N'-(beta-substituted ethyl)thiourea, followed by heating in a suitable solvent to close the thioazoline ring. Alternatively, the thiourea can be prepared by reaction between an appropriate aryl thiocyanate and an appro 25 priate alkylamine followed by the ring closure. In the foregoing procedures, the reaction between the amine and thiocyanate can conveniently be carried out (4) in a suitable inert organic solvent including both aromatic 30 and aliphatic hydrocarbon solvents. Halogenated, oxy -N - C genated or nitrated hydrocarbon solvents are useful. ( Representative solvents are benzene, chloroform, carbon tetrachloride, ethylene dichloride, chlorobenzene, toluene, xylene, nitrobenzene, and nitrotoluene. Temperatures in the range from 0 to 110° C. are suitable. (5) By reference to the reaction described above, it can be seen that in the ordinary practice of the process of

--- the invention, the thiazolines, and the imidazolines pro N H C duced will be hydrobromides, hydrochlorides, hydriodides, C methanesulfonic acids or p-toluenesulfonic acids. These 40 acids can be converted to other pharmaceutically accept A.< Y able acids by procedures well known to those skilled in the art. One highly useful method comprises contacting the (6) acid addition salt with a basic anion exchange resin, for example, a highly basic compound such as the one avail NE -C able from Rohm & Haas Company under the name "Am berlite IRA-400." This resin is a polyguaternary ammoni B Y-/ -R2 um compound which is prepared by chloromethylating a highly cross-linked copolymer of styrene and divinylben Zene followed by treatment of the chloromethylated ma In each of the above formulas, X is S or N; R, R, 50 terial with a tertiary amine such as trimethylamine. To R2 and R3 are the same or different and can each be prepare an acid addition salt of this invention, for exam hydrogen or an alkyl group of 1 through 4 carbons ple, the citrate, the resin is first contacted with an aqueous with the total number of carbons in these 4 substituents solution of citric acid whereupon an anion exchange takes being a maximum of 8. In the compounds of Formulas place converting the quaternary halide to the citrate. The 1 through 5, the hydrogen atoms in the naphthyl, the 55 citrate resin is then contacted with an acid addition salt partially reduced naphthyl or the indanyl groups may be prepared as described above and a further anion exchange replaced with substituents such as halogen, e.g., chlorine, takes place converting the acid addition salt to the citrate bromine, fluorine and iodine, alkyl of 1 through 4 car and leaving the anion of the orginial salt on the resin. bons, alkoxy of 1 through 4 carbons, alkylthio of 1 The citrate salt can be recovered from the eluate by a through 4 carbons, trifluoromethyl and trifluoromethoxy. 60 number of methods such as evaporation or solvent pre Up through three such substituents can be present. cipitation. This same procedure can be used to prepare In Formula 6, A can be hydrogen, alkyl of 1 through nitrates, sulfates, acetates and other acid addition salts. 4 carbons and preferably 1 or 2 carbons, alkoxy of Illustrative of the compounds within the scope of 1 through 4 carbons, and preferably 1 or 2 carbons, Formula 1 above are the following: or halogen including chlorine, bromine and fluorine: B 65 can be alkyl of 1 through 4 carbons and preferably 1 2-(3,4-dichloro-1-naphthylamino)-2-thiazoline or 2 carbons, alkoxy of 1 through 4 carbons and pref 2-(3,4-dichloro-1-naphthylamino)-2-imidazoline erably 1 or 2 carbons, or halogen including chlorine, 2-(3-bromo-1-naphthylamino)-4-metthyl-2-thiazoline bromine and fluorine; and C can be hydrogen, alkyl of 2-(3-brono-1-naphthylamino)-4-methyl-2-imidazoline. 1 through 4 carbons and preferably 1 or 2 carbons, 2-(4-ethyl-1-naphthylamino)-4,5-dimethyl-2-thiazoline alkoxy of 1 through 4 carbons and preferably 1 or 2 2-(4-ethyl-1-naphthylamino)-4,5-dimethyl-2-imidazoline carbons, halogen including chlorine, bromine and fluo 2-(3,4,5-triiodo-1-naphthylamino)-2-thiazoline rine, alkylthio of 1 through 4 carbons and preferably 1 2-(3,4,5-triiodo-1-naphthylamino)-2-imidazoline or 2 carbons, alkoxyalkyl wherein the alkoxy portion 2-(3,4-bismethylthio-1-naphthylamino)-4-butyl-2- has 1 or 2 carbons and the alkyl portion has 1 or 2 5 thiazoline

3,636,219 7 8 2-(5,6,7,8-tetrahydro-3,4,5-triiodo-1-naphthylamino)-4,5- 2-(2,5-diethoxyanilino)-2-thiazoline dimethyl-2-imidazoline 2-(2,5-diethoxyanilino)-2-imidazoline 2-(5,6,7,8-tetrahydro-4-isopropyl-1-naphthylamino)-2- 2-(3-chloro-4-methylanilino)-2-thiazoline thiazoline 2-(3-chloro-4-methyianilino)-2-imidazoline 2-(5,6,7,8-tetrahydro-4-isopropyl-1-naphthylamino)-2- 5 2-(2,6-diethylanilino)-2-thiazoline imidazoline 2-(2,6-diethylanilino)-2-imidazoline 2-(5,6,7,8-tetrahydro-4-trifluoromethyl-1-naphthylamino)- 2-(4-chloro-2-trifluoromethylanilino)-2-thiazoline 2-thiazolines 2-(4-chloro-2-trifluoromethylanilino)-2-imidazoline 2-(5,6,7,8-tetrahydro-4-trifluoromethyl-1-naphthylamino)- 2-(3-chloro-4-fluoroanilino)-2-thiazoline 2-imidazoline O 2-(3-chloro-4-fluoroanilino)-2-imidazoline 2-(5,6,7,8-tetrahydro-4-trifluoromethoxy-1-naphthyl 2-(4-fluoro-2-methylanilino)-2-thiazoline amino)-2-thiazolines 2-(4-fluoro-2-methylanilino)-2-imidazoline 2-(5,6,7,8-tetrahydro-4-trifiuoromethoxy-1-naphthyl amino)-2-imidazoline In the practice of the present invention it should be fully appreciated that administration of the anticholinergic Illustrative of the compounds within the scope of For and the thiazolines and the imidazolines for the intended mula 5 above are the following: profound depressant effect will be more or less concur 2-(4-indanylamino)-2-thiazoline rent, i.e., united in action, and not necessarily simul 2-(4-indanylamino)-2-imidazoline taneously, i.e., in the same pharmaceutical formulation 2-(2-chloro-4-indanylamino)-2-thiazoline or dosage unit. Thus, it will be understood that the syn 2-(2-chloro-4-indanylamino)-2-imidazoline ergistic benefits of the present invention will be readily 2-(2,5-diiodo-4-indanylamino)-2-thiazoline obtainable even though either one or the other of the two 2-(2,5-diiodo-4-indanylamino)-2-imidazoline essential materials may be administered somewhat prior 2-(3,5-bispropylthio-4-indanylamino)-2-thiazoline to or subsequent to the administration of the other. For 2-(3,5-bispropylthio-4-indanylamino)-2-imidazoline example, for gradual inducement of profound central 2-(2-methyl-4-indanylamino)-2-thiazoline nervous system depression with apparent unconsciousness 2-(2-methyl-4-indanylamino)-2-imidazoline in a patient, it may under some circumstances be desir Illustrative of the compounds within the scope of able to administer first the thiazoline or the imidazoline, Formula 6 are the following: perhaps orally, followed by within say 30 minutes or an 2-(2-toluidino)-2-thiazoline 30 hour by administration, perhaps by injection, of the syn 2-(2-toluidino)-2-imidazoline ergistic amount of the anticholinergic agent. 2-(2,3-dimethylanilino)-2-thiazoline Of course, the precise length of time which can elapse 2-(2,3-dimethylanilino)-2-imidazoline between administration of the anticholinergic and the 2-(3-chloro-2-methylanilino)-2-thiazoline thiazoline or the imidazoline, or vice versa, to still obtain 2-(3-chloro-2-methylanilino)-2-imidazoline the synergistic co-action of the compounds has not been 2-(2-ethylanilino)-2-thiazoline determined for each combination of the two different 2-(2-ethylanilino)-2-imidazoline materials possible according to this invention. This precise 2-(3,4-dimethylanilino)-2-thiazoline time lag will depend on the amount of each administered, 2-(3,4-dimethylanilino)-2-imidazoline the condition of the recipient, the absorption character 2-(3-isopropylanilino)-2-thiazoline 40 istics of each material, the dosage form or method, the 2-(3-isopropylanilino)-2-imidazoline nature of the effect desired, etc., as will be determined by 2-(2,3,4-trichloroanilino)-2-thiazoline the attendant physician or veterinarian. Generally speak 2-(2,3,4-trichloroanilino)-2-imidazoline ing, it is believed that provided the dosage of each are suf 2-(4-methoxy-2-methylanilino)-2-thiazoline ficient, the synergistic action is obtainable if the two com 2-(4-methoxy-2-methylanilino)-2-imidazoline ponents are administered within, say, 2 or 3 hours of each 5-methyl-2-(2,3-dimethyianilino)-2-thiazoline other. 5-methyl-2-(2,3-dimethylanilino)-2-imidazoline The amount of each of the two essential materials to be 4-ethyl-2-(2,3-dimethylanilino)-2-thiazoline administered will of course also depend upon the variables 4-ethyl-2-(2,3-dimethylanilino)-2-imidazoline just mentioned but, in general, the thiazoline or imidazol 4,4-dimethyl-2-(2-methyl-3-chloroanilino)-2-thiazoline 50 line will be administered in the range of about 0.1 to 100 4,4-dimethyl-2-(2-methyl-3-chloroanilino)-2-imidazoline milligrams per dose and in the range of about 0.1 to 500 5-butyl-2-(2-methylanilino)-2-thiazoline milligrams per day. For the synergistic effect, for each 5-butyl-2-(2-methylanilino)-2-imidazoline part by weight of thiazoline or imidazoline used, there 2-(2-dimethylaminoanilino)-2-thiazoline will usually be used from about 0.5 to about 30 parts by 2-(2-dimethylaminoanilino)-2-imidazoline 5 5 weight of anticholinergic agent, and preferably about 0.5 2-(3-methylthioanilino)-2-thiazoline to about 5 parts by weight of the latter. The absolute 2-(3-methylthioanilino)-2-imidazolinine potency of each of the ingredients will of course be the 2-(2-trifluoromethylanilino)-2-thiazoline prime determining factors. 2-(2-trifiuoromethylanilino)-2-imidazoline As mentioned above, in general, the physician or 2-(2-trifluoromethoxy-3-methylanilino)-2-thiazoline 60 veterinarian will, of course, determine the dosage of each 2-(2-trifluoromethoxy-3-methylanilino)-2-imidazoline and the total dosage which will be most suitable for a 2-(2,4,5-trimethylanilino)-2-thiazoline particular application, and as might be expected, it will 2-(2,4,5-trimethylanilino)-2-imidazoline vary with the age, weight and general health of the 4-methyl-2-(2-methyl-5-isopropylanilino)-2-thiazoline patient under treatment and with various other factors 4-methyl-2-(2-methyl-5-isopropylanilino)-2-imidazoline which will be determined by the physician or veterinarian 2-(2,5-dimethoxyanilino)-2-thiazoline in attendance. When they are administered orally a larger 2-(2,5-dimethoxyanilino)-2-imidazoline quantity will be required to produce the same effect as 5-methyl-2-(2,4-dimethoxy-5-chloroanilino)-2- a smaller quantity given parenterally. Parenteral ad ministration of from 0.1 mg. to 250 mg. of each active 5-methyl-2-(2,4-dimethoxy-5-chloroanilino)-2-thiazoline agent should be suitable to obtain some effect. Adminis imidazoline tration can also be by vapor or spray through the mouth 2-(2-fluoroanilino)-2-thiazoline or nasal passages. 2-(2-fluoroanilino)-2-imidazoline In animal tests to date no synergism of cardiovascular 2-(2-bromo-4-methylanilino)-2-thiazoline actions has thus far been noted. Furthermore, based on 2-(2-bromo-4-methylanilino) -2-imidazoline 75 tests to date, it is believed that the surprising Synergism 3,636,219 9 10 in inducement of profound central nervous system de After mixing, the mixture is screened through a 40 mesh pression obtained according to the present invention is Screen and encapsulated in No. 3 two-piece hard gelatin achieved without at the same time substantially altering capsules. the normally expected effect of centrally acting anti EXAMPLE 3 cholinergic agents on the heart rate. 5 In the practice of this invention, the active pharma The active ingredients of Example 1 (20 parts by ceutical agents may be administered alone but are gen Weight) is dispersed in 100 parts by volume of corn erally administered with a pharmaceutical carrier se oil and encapsulated in standard soft gelatin capsules. lected on the basis of the chosen route of administra EXAMPLE 4 tion and standard pharmaceutical practice. For exam O ple, they may be administered orally in the form of The active ingredients of Example 2 (20 parts by tablets or capsules containing such excipients as starch, Weight) is dispersed in 100 parts by volume of corn oil milk sugar, certain types of clay, etc. They may be ad and encapsulated in standard soft gelatin capsules. ministered orally in the form of elixirs or oral suspen sions which may contain coloring and flavoring agents. EXAMPLE 5 They may be injected parenterally and for this use may Tablets for oral administration are prepared by mixing be prepared in the form of sterile aqueous solutions con 50 milligrams of the active ingredients of Example 1, 2.5 taining other solutes such as saline or glucose in suffi milligrams of gelatin, 2.5 milligrams of magnesium cient quantity to make the solution of isotonic. For intra Stearate and 100 milligrams of starch, and forming the muscular administration compositions of the compounds mixture into tablets by a conventional tableting machine. of this invention may be prepared in an oil base such as Slow release pills and tablets can also be used. peanut or sesame oil. Compositions useful in the practice of the present in EXAMPLE 6 vention may take a variety of forms. Various diluents may be employed and the percentage of active ingre Tablets for oral administration are prepared by mixing dients may be varied. It is necessary that the active in 50 milligrams of the active ingredients of Example 2, 2.5 gredient or ingredients form a proportion of the com milligrams of gelatin, 2.5 milligrams of magnesium stea position such that a suitable dosage form will be ob rate and 100 milligrams of starch, and forming the mix tained. Obviously several dosage unit forms can be ad ture into tablets by a conventional tableting machine. Slow ministered at about the same time. Although composi release pills and tablets can also be used. tions with less than 0.005% by weight of either active ingredient are suitable, it is preferred to use composi EXAMPLE 7 tions containing not less than 0.005% of either active agent because otherwise the amount of carrier becomes A parenteral composition suitable for administration excessively large. Activity normally increases with the 3 3. by injection is prepared by dissolving 5% by weight of concentration of the active agent. The percentage by the active ingredients of Example 1 in 95% by volume of weight of single or combined active agents can be 10, 50, physiological saline and sterilizing the resultant solution 75, 95% or even higher. Dosage unit forms may be pre by filtration. A buffer can be used if desired. pared with a minor proportion of a carrier and a major proportion of active materials and vice versa. 40 EXAMPLE 8 The following examples are given solely for the pur A parenteral composition suitable for administration pose of illustration and are not to be construed as limita by injection is prepared by dissolving 5% by weight of the tions of this invention, many variations of which are pos active ingredients of Example 2 in 95% by volume of sible without departing from the spirit or scope thereof. physiological saline and sterilizing the resultant solution EXAMPLE by filtration. A buffer can be used if desired. A large number of unit capsules are prepared for oral EXAMPLE 9 administration by mixing the following ingredients: 2-(5,6,7,8-tetrahydro-1-naphthylamino) - 2 - thiazoline Parts by weight (0.2 part by weight) is dissolved at a concentration of 2-(5,6,7,8 - tetrahydro - 1 - naphthylamino) - 2 2 milligrams per milliliter in a mixture of 25 parts by thiazoline ------650 Weight of polyethylene glycol ("Carbowax' 400) and 75 Scopolamine hydrobromide ------1,300 parts by Weight of physiological saline. The resulting solu Lactose U.S.P. ------8,000 tion is then combined with an equal volume of a solution Dry pyrogenic silica SiO2 with particle size of 5 5 of 4 milligrams of atropine sulfate dissolved in 1 milliliter 0.015 micron, surface area of 200 m2/gm., and of physiological Saline. The combined solution is injected bulk density of 2.2 lbs./cu. ft. ("Cabosil,' into the cephalic vein of a 2 year old beagle dog so that Cabot Corp.) ------50 a total of 0.1 milligram of the thiazoline and 0.2 milli After mixing, the mixture is screened through a 40 gram of the atropine Sulfate, per kilogram of body weight mesh screen and encapsulated in No. 3 two-piece hard 60 of the dog, is administered. In about 15 minutes the gelatin capsules. animal becomes depressed and passes into a state of deep central nervous system depression in which the animal EXAMPLE 2. does not respond to painful stimuli. This state lasts for A large number of unit capsules are prepared by oral about 1 to 2 hours following which the animal recovers administration by mixing the following ingredients: normal functions with no deleterious after-effects. Parts by weight EXAMPLE 10 2-(5,6,7,8 - tetrahydro - 1 - naphthylamino) - 2 imidazoline ------650 2 - (5,6,7,8-tetrahydro-1-naphthylamino)-2-imidazoline Scopolamine hydrobromide ------1,300 O (0.2 part by weight) is dissolved at a concentration of Lactose U.S.P. ------8,000 2 milligrams per milliliter in a mixture of 25 parts by Dry pyrogenic silica SiO2 with particle size of weight of polyethylene glycol ("Carbowax' 400) and 0.015 micron, surface area of 200 m.2/gm., and 75 parts by Weight of physiological saline. The result bulk density of 2.2 lb./cu. ft. ('Cabosil,' ing Solution is then combined with an equal volume Cabot Corp.) ------50 75 of a Solution of 4 milligrams of atropine sulfate dissolved 3,636,219 2 in 1 milliliter of physiological saline. The combined solu old male dog in an amount to introduce 0.132 milligram tion is injected into the cephalic vein of a 2 year old of imidazoline per kilogram of body weight of the dog. beagle dog so that a total of 0.1 milligram of the imidazo This injection is followed in 10 minutes by intravenous line and 0.2 milligram of the atropine sulfate, per kilo administration of a normal saline solution of atropine gram of body weight of the dog, is administered. In about sulfate, sufficient to introduce 0.5 milligram of atropine 15 minutes the animal becomes depressed and passes into Sulfate per kilogram of body weight of the dog. In about a state of deep central nervous system depression in which 5 minutes the animal becomes depressed and passes into the animal does not respond to painful stimuli. This state a state of deep central nervous system depression in lasts for about 1 to 2 hours following which the animal which the animal does not respond to painful stimuli. This recovers normal functions with no deleterious after-effects. O state lasts for about 1 to 2 hours following which the animal recovers normal functions with no deleterious EXAMPLE 1. after-effects. A 1 year old female dog is given an intravenous in EXAMPLE 1.5 jection of atropine sulfate dissolved in 0.4% by weight concentration in physiological saline. The injection is suf Example 13 is repeated, except that scopolamine hydro ficient to introduce 0.2 milligram of the atropine sulfate bromide is used in place of the atropine Sulfate, with per kilogram of body weight of the dog. The injection similar results. of atropine sulfate is followed 10 minutes later by intra EXAMPLE 16 venous injection of 2 - (5,6,7,8 - tetrahydro-1-naphthyl Example 14 is repeated, except that scopolamine hydro amino)-2-thiazoline, dissolved in 0.2% by weight con bromide is used in place of the atropine Sulfate, with centration in polyethylene glycol (25 parts) and physio similar results. logical saline (75 parts), in amount sufficient to introduce EXAMPLE 17 0.1 milligram of the thiazoline per kilogram of body Example 11 is repeated, except that in place of the weight. In about 15 minutes the animal becomes depressed atropine sulfate there is used an amount of phenyl cyclo and passes into a state of deep central nervous system pentylglycolic acid, N-ethylpiperidino ester, Sufficient to depression in which the animal does not respond to pain introduce 0.2 milligram of the ester per kilogram of body ful stimuli. This state lasts for about 1 to 2 hours follow weight of the dog, with similar results. ing which the animal recovers normal functions with no deleterious after-effects. EXAMPLE 8 30 Example 12 is repeated, except that in place of the EXAMPLE 12 atropine sulfate there is used an amount of phenyl cyclo A 1 year old female dog is given an intravenous in pentylglycolic acid, N-ethylpiperidinol ester, sufficient to jection of atropine sulfate dissolved in 0.4% by weight introduce 0.2 milligram of the ester per kilogram of body concentration in physiological saline. The injection is suf weight of the dog, with similar results. ficient to introduce 0.2 milligram of the atropine sulfate EXAMPLE 1.9 per kilogram of body weight of the dog. The injection of Example 9 is repeated, except that in place of the atropine sulfate is followed 10 minutes later by intra atropine there is used an amount of benzilic acid, beta venous injection of 2 - (5,6,7,8 - tetrahydro-1-naphthyl diethylaminoethyl ester, sufficient to introduce 0.1 milli amino) - 2 - imidazoline, dissolved in 0.2% by weight concentration in polyethylene glycol (25 parts) and 40 gram of the ester per kilogram of body weight of the physiological saline (75 parts), in amount sufficient to dog, with similar results. introduce 0.1 milligram of the imidazoline per kilogram EXAMPLE 2.0 of body weight. In about 15 minutes the animal becomes Example 10 is repeated, except that in place of the depressed and passes into a state of deep central nervous atropine there is used an amount of benzilic acid, beta system depression in which the animal does not respond diethylaminoethyl ester, sufficient to introduce 0.1 milli to painful stimuli. This state lasts for about 1 to 2 hours gram of the ester per kilogram of body Weight of the dog, following which the animal recovers normal functions with similar results. with no deleterious after-effects. EXAMPLE 21 EXAMPLE 3 Rhesus monkeys are exposed for 5 minutes in a dynam ic chamber to an atmosphere containing 400 micrograms 2-(2,3-dimethylanilino)-2-thiazoline (3 parts by weight) per liter of 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2- is dissolved in 1000 parts by weight of a mixture of 25 thiazoline and 800 micrograms per liter of Scopolamine parts by weight of polyethylene glycol (“Carbowax' 400) 5 5 aspirated into the chamber in the form of an aerosol. and 75 parts by weight of physiological saline. The result Within 3 to 5 minutes the animals become prostrate, ing solution is injected intravenously into a two year-old severely depressed and apparently unconscious for a period male dog in an amount to introduce 0.132 miligram of of about 1 hour. thiazoline per kilogram of body weight of the dog. This EXAMPLE 22 injection is followed in 10 minutes by intravenous ad Iministration of a normal saline solution of atropine 60 Rhesus monkeys are exposed for 5 minutes in a dy sulfate, sufficient to introduce 0.5 milligram of atropine namic chamber to an atmosphere containing 400 micro sulfate per kilogram of body weight of the dog. In about grams per liter of 2-(5,6,7,8-tetrahydro-1-naphthyl 15 minutes the animal becomes depressed and passes into amino)-2-imidazoline and 800 micrograms per liter of a state of deep central nervous system depression in which scopolamine aspirated into the chamber in the form of an the animal does not respond to painful stimuli. This state aerosol. Within 3 to 5 minutes the animals become pros lasts for about 1 to 2 hours following which the animal trate, severely depressed and apparently unconscious for recovers normal functions with no deleterious after-effects. a period of about 1 hour. EXAMPLES 23-52 EXAMPLE 14 The procedures of Examples 9, 10, 11 and 2 are re 2- (2,3-dimethyianilino)- 2 - imidazoline (3 parts by peated except that the following listed anticholinergic weight) is dissolved in 1000 parts by weight of a mixture agents and thiazolines or imidazolines are substituted in of 25 parts by weight of polyethylene glycol ("Carbowax like amounts by weight for those of Examples 9, 10, 11 400) and 75 parts by weight of physiological saline. The and 12 respectively. They are administered in like manner resulting solution is injected intravenously into a 2 year and provide like results. 3,636,219

Amount Almount (mg/kg.) (mg./kg.) Anticholinergic 0.25 2-(1-naphtylamino)-2-thiazoline-- 0. 500 Atropine sulfate. 0.25 2-(1-naphthylamino)-2-imidazolin 0.500 Do. 0.2 2-(4-methoxy-1-naphthylamino)-2-thiazoline-- 0.400 Scopolamine hydrobromide. 0.2 2-(4-methoxy--naphthylamino)-2-imidazoline-- 0.400 Do. 0.2 2-(4-methoxy-1-naphthylamino)-2-thiazoline---- 5.00 Benzety zine. 0.2 2-(4-methoxy-i-naphthylamino)-2-imidazoline.-- 5.00 D0. 0.2 2-(2-methyl-1-naphthylamino)-2-thiazoline------0.400 Scopolamine hydrobromide. 0.2 2-(2-methyl-1-naphthylamino)-2-imidazoline------0.400 D0. 1.0 2-(4-methyl-1-naphthylamino)-2-thiazoline------1.00 Atropine sulfate. 1.0 2-(4-methyl-1-naphthylamino)-2-midazoline----- 1, 00 ID 0. 0.1 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-thiazoline. 0, 00 Trasentine, 0.1 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-imidazoline------10.00 Do. 0.1 2-(4-methyl-5,6,7,8-tetrahydro-1-naphthylamino)-2-thiazoline----- 0.50 Benztropine. 0.1 2-(4-methyl-5,6,7,8-tetrahydro-1-naphthylamino)-2-imidazoline--- 0,50 D0. 0. 5 2-(4-methoxy-5,6,7,8-tetrahydro-1-naphthylamino)-2-thiazoline.-- 1.00 Ditran. 0. 5 2-(4-methoxy-5,6,7,8-tetrahydro-1-naphthylamino)-2-imidazoline- 1.00 Do. 0. 2-(1,2,3,4-tetrahydro-1-naphthylamino)-2-thiazoline------25.00 Caramiphen 0. 2-(1,2,3,4-tetrahydro-1-naphthylamino)-2-imidazoline 25.00 Do. 0.25 2-(2-methylanilino)-2-thiazoline------0. 50 Cyclopentolate. 0.25 2-(2-methylanilino)-2-imidazoline 0.50 Do. 0. 5 2-(2-ethylanilino)-2-thiazoline--- 5.00 Cycrimine hydrochloride. 0. 5 2-(2-ethylanilion)-2-imidazoline------5.00 Do. 0.1 2-(2,3-dimethylanilino)-2-thiazoline------50.00 Ethopropazine. 0.1 2-(2,3-dimethylanilino)-2-imidazoline- - - - - 50.00 Do. 0.25 2-(2-chloro-2-methylanilino)-2-thiazoline------50, 00 Piparidolate. 0.25 2-(2-chloro-2-methylanilino)-2-imidazoline--- 50.00 Do. 0. 2-(2,6-dimethylanilino)-2-thiazoline------20.00 Oxyphencyclimine. 0.1 2-(2,6-dimethylanilino)-2-imidazoline.----- 20, 00 Do. 0.75 2-(4-methoxy-2-methylanilino)-2-thiazoline- 5.00 Tricyclamo.

0.75 2-(4-methoxy-2-methylanilino)-2-imidazoline 5.00 Do. Pharmaceutically acceptable acid addition salts of 2 where in each of Formulas 1 through 6 X is selected arylamino-2-thiazolines and 2-arylamino-3-imidazolines from the group consisting of sulfur and nitrogen; R, R, provide results equivalent to that of the 2-arylamino-2- R and R3 are each separately selected from the group thiazolines and 2-arylamino-2-imidazolines. consisting of hydrogen and alkyl of 1 through 4 carbons The invention claimed is: with the total number of carbons in these four substituents 1. The method comprising administering to a warm being a maximum of 8; where in each of Formulas 1. blooded animal two essential substances within three hours 30 through 5, 1 through 3 hydrogen atoms of the moiety of each other, the first essential substance being 0.5 to 30 selected from the group consisting of naphthyl, partially parts by weight of a centrally acting anti-cholinergic agent reduced naphthyl and indanyl can be replaced with a mem and the second essential substance being 1 part by weight ber selected from the group consisting of halogen, alkyl of a compound selected from the group consisting of of 1 through 4 carbons, alkoxy of 1 through 4 carbons, alkylthio of 1 through 4 carbons, trifluoromethly and tri fluoromethoxy; and wherein. Formula 6A is selected from the group consisting of hydrogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons and halogen; B is selected from the group consisting of alkyl of 1 40 through 4 carbons, alkoxy of 1 through 4 carbons and halogen; and C is selected from the group consisting of hy drogen, 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 carbons, alkylamino of 1 through 2 carbons, dialkylamino where each alkyl group has 1 through 2 carbons, trifluoromethyl and trifluoromethoxy. 2. The method according to claim 1 wherein said 50 centrally acting anticholinergic is N-ethyl-3-piperidyl phenylcyclopentyl glycolate. 3. The method comprising administering to a warm blooded animal within an hour of each other from 0.5 to 30 parts by weight of a centrally acting anticholinergic 5 5 agent and 1 part by weight of a compound of the formula

60 k Where X is selected from the group consisting of sulfur and nitrogen; R, R, R and R3 are each selected from the group consisting of hydrogen and alkyl of 1 through 4 carbons with the total number of carbons in each of these 4 substituents being a maximum of 8; and where 1 through 3 of the hydrogen atoms in the naphthyl group 70 can be replaced with a member selected from the group consisting of halogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons, alkylthio of 1 through 4 carbons, trifluoromethyl and trifluoromethoxy. 4. The method comprising administering to a warm 75 blooded animal within an hour of each other from 0.5 3,636,219 5 6 to 30 parts by weight of a centrally acting anticholinergic 4 carbons with the total number of carbons in each- of agent and 1 part by weight of a compound of the formula these 4 substituents being a maximum of 8; and where 1 through 3 of the hydrogen atoms in the indanyl group i can be replaced with a member selected from the group X-C-Ri consisting of halogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons, alkylthio of 1 through 4 carbons, trifluoromethyl and trifluoromethoxy. 8. The method comprising administering to a warm where X is selected from the group consisting of sulfur blooded animal within an hour of each other 0.5 to 30 and nitrogen; R, R, R2 and R3 are each selected from O parts by weight of a centrally acting anticholinergic agent the group consisting of hydrogen and alkyl of 1 through 4 and 1 part by weight of a compound of the formula carbons with the total number of carbons in each of these 4 substituents being a maximum of 8; and where through 3 of the hydrogen atoms in the partially re | duced naphthyl group can be replaced with a member 5 A. x--R selected from the group consisting of halogen, alkyl of -NH-C 1 through 4 carbons, alkoxy of 1 through 4 carbons, B XD S N-C-R2 alkylthio of 1 through 4 carbons, trifluoromethyl and k trifluoromethoxy. 5. The method comprising administering to a warm 20 where X is selected from the group consisting of sulfur blooded animal within an hour of each other, from 0.5 and nitrogen; R, R, R2 and R3 are each selected from to 30 parts by weight of a centrally acting anticholinergic the group consisting of hydrogen and alkyl of 1 through agent and 1 part by Weight of a compound of the formula 4 carbons with the total number of carbons in each of these 4 substituents being a maximum of 8; A is selected from the group consisting of hydrogen, alkyl of through X--R 4 carbons, alkoxy of 1 through 4 carbons and halogen; B is selected from the group consisting of alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons and halogen; and C is selected from the group consisting of 30 hydrogen, alkyl of 1 through 4 carbons, alkoxy of 1 where X is selected from the group consisting of sulfur through 4 carbons, halogen, alkylthio of 1 through 4 car and nitrogen; R, R, R2 and R3 are each selected from the bons, alkoxyalkyl wherein the alkoxy portion has 1 group consisting of hydrogen and alkyl of 1 through 4 through 2 carbons and the alkyl portion has 1 through 2 carbons with the total number of carbons in each of carbons, alkylamino of 1 through 2 carbons, dialkylamino these 4 substituents being a maximum of 8; and where where each alkyl group has through 2 carbons, tri 1 through 3 of the hydrogen atoms in the indanyl group fluoromethyl and trifluoromethoxy. can be replaced with a member selected from the group 9. The method according to claim.1 where said anti consisting of halogen, alkyl of 1 through 4 carbons, cholinergic agent is atropine sulfate and the second in alkoxy of through 4 carbons, alkylthio of 1 through 4 gredient is 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-thia carbons, trifluoromethyl and trifluoromethoxy. 40 Zoline. 6. The method comprising administering to a warm 10. The method according to claim 1 where said anti blooded animal within an hour of each other, 0.5 to 30 cholinergic agent is atropine sulfate and the second in parts by weight of a centrally acting anticholinergic gredient is 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-imi agent and 1 part by weight of a compound of the formula dazoline. 45 11. The method according to claim where said anti cholinergic agent is atropine sulfate and the second in gredient is 2-(2,3-dimethyianilino)-2-thiazoline. 12. The method according to claim 1 where said anti cholinergic agent is atropine sulfate and the second in 50 gredient is 2-(2,3-dimethylanilino)-2-imidazoline. 13. The method according to claim 1 where said anti where X is selected from the group consisting of sulfur cholinergic agent is scopolamine hydrobromide and the and nitrogen; R, R1, R2 and R3 are each selected from second ingredient is 2-(5,6,7,8-tetrahydro - 1 - naphthyl the group consisting of hydrogen and alkyl of 1 through amino)-2-thiazoline. 4 carbons with the total number of carbons in each of 55 14. The method according to claim where said anti these 4 substituents being a maximum of 8; and where cholinergic agent is scopolamine hydrobromide and the 1 through 3 of the hydrogen atoms in the partially re second ingredient is 2-(5,6,7,8-tetrahydro - 1 - naphthyl duced naphthyl group can be replaced consisting of halo amino)-2-imidazoline. - gen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 5. The method according to claim where said anti carbons, alkylthio of 1 through 4 carbons, trifluoromethyl 60 cholinergic agent is scopolamine hydrobromide and the and trifluoromethoxy. second ingredient is 2-(2,3-dimethylanilino)-2-thiazoline. 7. Method comprising administering to a warm-blooded 6. The method according to claim 1 where said anti animal within an hour of each other, 0.5 to 30 parts by cholinergic agent is scopolamine hydrobromide and the weight of a centrally acting anticholinergic agent and 1 second ingredient is 2-(2,3-dimethylanilino)-2-imidazo part by weight of a compound of the formula 65 line. 17. The method according to claim where said anti cholinergic agent is selected from the group consisting of phenylcyclopentylglycolic acid, N-ethylpiperidinol ester and benzilic acid, beta diethylaminoethyl ester and the second ingredient is 2-(5,6,7,8-tetrahydro - 1 - naphthyl amino)-2-thiazoline. '. 18. The method according to claim 1 where said anti where X is selected from the group consisting of sulfur cholinergic agent is selected from the group consisting of and nitrogen; R, R, R2 and R3 are each selected from phenylcyclopentylglycolic acid, N-ethylpiperidinol ester the group consisting of hydrogen and alkyl of 1 through and benzilic acid, beta diethylaminoethyl ester and the 3,636,219 7 18 second ingredient is 2-(5,6,7,8-tetrahydro - 1 - naphthyl and amino)-2-imidazoline. 19. The method according to claim 1 where said anti (6) R. cholinergic agent is selected from the group consisting of A. X-C-R1 phenylcyclopentylglycolic acid, N-ethylpiperidinol ester and benzilic acid, beta diethylaminoethyl ester and the second ingredient is 2-(2,3-dimethylanilino) - 2 - thiazo line. k 20. The method according to claim where said anti where in each of the Formulas 1 through 6 X is selected cholinergic agent is selected from the group consisting of 0 from the group consisting of sulfur and nitrogen; R, R, R phenylcyclopentylglycolic acid, N-ethylpiperidinol ester and R3 are each separately selected from the group con and benzilic acid, beta diethylaminoethyl ester and the sisting of hydrogen and alkyl of 1 through 4 carbons with second ingredient is 2-(2,3-dimethylanilino) - 2 - imidazo the total number of carbons in these four substituents be line. ing a maximum of 8; where in each of Formulas 1. 21. The method according to claim 1 where said anti through 5, 1 through 3 hydrogen atoms in the moiety cholinergic agent is selected from the group consisting of Selected from the group consisting of naphthyl, partially phenylcyclopentylglycolic acid, N-ethylpiperidinol ester reduced naphthyl and indanyl can be replaced with a and benzilic acid, beta diethylaminoethyl ester and the member selected from the group consisting of halogen, second ingredient is 2-(5,6,7,8-tetrahydro - 1 - naphthyl alkyl of 1 through 4 carbons, alkoxy of 1 through 4 car amino)-2-thiazoline. bons, alkylthio of 1 through 4 carbons, trifluoromethyl 22. The method according to claim where said anti and trifluoromethoxy; and where in Formula (6) A is se cholinergic agent is selected from the group consisting of lected from the group consisting of hydrogen, alkyl of 1 phenylcyclopentylglycolic acid, N-ethylpiperidinol ester through 4 carbons, alkoxy of 1 through 4 carbons and and benzilic acid, beta diethylaminoethyl ester and the halogen; B is selected from the group consisting of alkyl second ingredient is 2-(5,6,7,8-tetrahydro - 1 - naphthyl 2 5 of 1 through 4 carbons, alkoxy of 1 through 4 carbons and amino)-2-imidazoline. halogen; and C is selected from the group consisting of hy 23. The method according to claim where said anti drogen, alkyl of 1 through 4 carbons, alkoxy of 1 through cholinergic agent is selected from the group consisting of 4 carbons, halogen, alkylthio of 1 through 4 carbons, al phenylcyclopentylglycolic acid, N-ethylpiperidinol ester koxyalkyl wherein the alkoxy portion has 1 through 2 car and benzilic acid, beta diethylaminoethyl ester and the 30 bons and the alkyl portion has 1 through 2 car second ingredient is 2-(2,3-dimethylanilino)-2-thiazoline. bons, alkylamino of 1 through 2 carbons, dialkylamino 24. The method according to claim 1 where said anti where each alkyl group has 1 through 2 carbons, trifluoro cholinergic agent is selected from the group consisting of methyl and trifluoromethoxy. phenylcyclopentylglycolic acid, N-ethylpiperidinol ester 26. A composition according to claim 25 where said and benzilic acid, beta diethylaminoethyl ester and the centrally acting anticholinergic agent is N-ethyl-3-piper second ingredient is 2-(2,3-dimethylanilino) - 2 - imidazo idylphenylcyclopentylglycolate. line. 27. A composition comprising from 0.5 to 30 parts by 25. A composition comprising from 0.5 to 30 parts by weight of a centrally acting anticholinergic agent and 1 weight of a centrally acting anticholinergic agent and 1 part by weight of a compound of the formula part by weight of a compound of the formula 40 (1) R X-C-Ri -N-C C 45

(2) where X is selected from the group consisting of sulfur and nitrogen; R, R, R2 and R3 are each selected from the group consisting of hydrogen and alkyl of 1 through 4 carbons with the total number of carbons in each of these 4 substituents being a maximum of 8; and where 1 through 3 of the hydrogen atoms in the naphthyl group can be re placed with a member selected from the group consisting (3) of halogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons, alkylthio of 1 through 4 carbons, tri fluoromethyl and trifluoromethoxy. 28. A composition comprising from 0.5 to 30 parts by 60 weight of a centrally acting anticholinergic agent and 1 part by weight of a compound of the formula (4) R R S.X-C-R1. (5)

where X is selected from the group consisting of sulfur and nitrogen; R, R, R2 and R3 are each selected from the group consisting of hydrogen and alkyl of 1 through 4 75 carbons with the total number of carbons in each of these 3,636,219 9 2 4 substituents being a maximum of 8; and where 1 through weight of a centrally acting anticholinergic agent and 1 3 of the hydrogen atoms in the partially reduced naphthyl part by weight of a compound of the formula group can be replaced with a member selected from the group consisting of halogen, alkyl of 1 through 4 car bons, alkoxy of 1 through 4 carbons, alkylthio of 1 R through 4 carbons, trifluoromethyl and trifluoromethoxy. A. x--R 29. A composition comprising from .5 to 30 parts by X.)w -NH-C NS weight of a centrally acting anticholinergic agent and 1 B N-C-R2 C part by weight of a compound of the formula R3 O where X is selected from the group consisting of sulfur and nitrogen; R, R1, R2 and R3 are each selected from the group consisting of hydrogen and alkyl of 1 through 4 carbons with the total number of carbons in each of these 4 substituents being a maximum of 8; A is selected from the group consisting of hydrogen, alkyl of 1 through 4 carbons, alkoxy of 1 through 4 carbons and halogen; B is selected from the group consisting of alkyl of 1 where X is selected from the group consisting of sulfur through 4 carbons, alkoxy of 1 through 4 carbons and and nitrogen; R, R, R2 and R3 are each selected from the 20 halogen; and C is selected from the group consisting of group consisting of hydrogen and alkyl of 1 through 4 hydrogen, alkyl of 1 through 4 carbons, alkoxy of 1 carbons with the total number of carbons in each of these through 4 carbons, halogen, alkylthio of 1 through 4 car 4 substituents being a maximum of 8; and where 1. bons, alkoxyalkyl wherein the alkoxy portion has 1 through 3 of the hydrogen atoms in the indanyl group through 2 carbons and the alkyl portion has 1 through 2 can be replaced with a member selected from the group 2. 5 carbons, alkylamino of 1 through 2 carbons, dialkylamino consisting of halogen, alkyl of 1 through 4 carbons, alk where each alkyl group has 1 through 2 carbons, trifluoro oxy of 1 through 4 carbons, alkylthio of 1 through 4 methyl and trifluoromethoxy. carbons, trifluoromethyl and trifluoromethoxy. 33. A composition comprising 1 part by Weight of 2 30. A composition comprising from 0.5 to 30 parts by (5,6,7,8-tetrahydro-1-naphthylamino)-2-thiazoline and weight of a centrally acting anticholinergic agent and 1 30 0.5-30 parts by weight of atropine sulfate. part by weight of a compound of the formula 34. A composition comprising 1 part by Weight of 2 (5,6,7,8-tetrahydro-1-naphthylamino)-2-imidazoline and 0.5-30 parts by weight of atropine sulfate. R 35. A composition comprising 1 part by weight of 2 X R 3 5 (2,3-dimethylanilino)-2-thiazoline and 0.5-30 parts by weight of atropine Sulfate. { X-N -- C A 36. A composition comprising 1 part by weight of 2 N-g-lef (2,3-dimethylanilino)-2-imidazoline and 0.5-30 parts by * R.3 weight of atropine sulfate. 40 37. A composition comprising 1 part by weight of 2 (5,6,7,8-tetrahydro-1-naphthylamino)-2-thiazoline and where X is selected from the group consisting of sulfur 0.5-30 parts by weight of scopolamine hydrobromide. and nitrogen; R, R, R and R3 are each selected from the 38. A composition comprising 1 part by Weight of 2 group consisting of hydrogen and alkyl of 1 through 4 (5,6,7,8-tetrahydro-1-naphthylamino)-2-imidazoline and carbons with the total number of carbons in each of these 45 0.5-30 parts by weight of scopolamine hydrobromide. 4 Substituents being a maximum of 8; and where I 39. A composition comprising 1 part by Weight of 2 through 3 of the hydrogen atoms in the partially reduced (2,3-dimethylanilino)-2-thiazoline and 0.5 to 30 parts by naphthyl group can be replaced consisting of halogen, weight of scopolamine hydrobromide. alkyl of 1 through 4 carbons, alkoxy of 1 through 4 car 40. A composition comprising 1 part by Weight of 2 bons, alkylthio of 1 through 4 carbons, trifluoromethyl (2,3-dimethylanilino)-2-imidazoline and 0.5 to 30 parts and trifluoromethoxy. 50 by weight of scopolamine hydrobromide. 31. A composition comprising from 0.5 to 30 parts by 41. A composition comprising 1 part by weight of 2 weight of a centrally acting anticholinergic agent and 1 (5,6,7,8-tetrahydro-1-naphthylamino) - 2 - thiazoline and part by Weight of a compound of the formula 0.5-30 parts by weight of a compound selected from the 55 group consisting of phenylcyclopentylglycolic acid, N ethylpiperidinol ester and benzilic acid, beta diethyl aminoethyl ester. 42. A composition comprising 1 part by weight of 2 X (5,6,7,8-tetrahydro-1-naphthylamino) - 2-imidazoline and 0.5–30 parts by weight of a compound selected from the 60 group consisting of phenylcyclopentylglycolic acid, N ethylpiperidinol ester and benzilic acid, beta diethylamino ethyl ester. 43. A composition comprising 1 part by weight of 2 where X is selected from the group consisting of sulfur (2,3-dimethylanilino)-2-thiazoline and 0.5-30 parts by and nitrogen; R, R, R2 and R3 are each selected from Weight of a compound selected from the group consisting the group consisting of hydrogen and alkyl of 1 through of phenylcyclopentylglycolic acid, N-ethylpiperidinol ester 4 carbons with the total number of carbons in each of and benzilic acid, beta diethylaminoethyl ester. these 4 substituents being a maximum of 8; and where 1 44. A composition comprising 1 part by weight of through 3 of the hydrogen atoms in the indanyl group O 2-(2,3-dimethylanilino)-2-imidazoline and 0.5-30 parts by can be replaced with a member selected from the group Weight of a compound selected from the group consisting consisting of halogen, alkyl of 1 through 4 carbons, alk of phenylcyclopentylglycolic acid, N-ethylpiperidinol ester oxy of 1 through 4 carbons, alkylthio of 1 through 4 and benZilic acid, beta diethylaminoethyl ester. carbons, trifluoromethyl and trifluoromethoxy. 45. A composition comprising 1 part by weight of 32. A composition comprising from 0.5 to 30 parts by 2-(5,6,7,8,-tetrahydro-1-naphthylamino)-2-thiazoline and 3,636,219 21 22 0.5-30 parts by weight of benzilic acid, beta-diethylamino References Cited ethyl ester. 46. A composition comprising 1 part by weight of UNITED STATES PATENTS 2-(5,6,7,8-tetrahydro-1-naphthylamino)-2-imidazoline and 3,287,469 11/1966 Harvey ------260-309.6 0.5–30 parts by weight of benzilic acid, beta-diethylamino- 5 2,027,031 1/1936 Engelmann ------260-44 ethyl ester. ) 2,870,160 1/1959 Bloom ------260-307 47. A composition comprising 1 part by weight of 3,287,469 11/1966 Harvy ------260-309.6 2-(2,3-dimethylanilino)-2-thiazoline and 0.5-30 parts by weight of benzilic acid, beta-diethylaminoethyl ester. LELAND A. SEBASTIAN, Primary Examiner 48. A composition comprising 1 part by weight of O U.S. C. X.R 2-(2,3-dimethylanilino)-2-imidazoline and 0.5-30 parts by 260-306.8 R, 309.6; 424-247, 251, 267,268,269, 270, weight of benzilic acid, beta-diethylaminoethyl ester. 273 and 274