US3264309A - N' [nu-(monocarbocyclic aryl) carbamyllower-alkyl]-1, 5-iminocycloalkanes, -iminocycloalkenes and related compounds - Google Patents

Description

United States Patent 3,264,309 N'[N-(MONOCARBOCYCLIC ARYL) CARBAMYL- LOWER-ALKYL] 1,5 lMINOCYCLOALKANES, -IMINOCYCLOALKENES AND RELATED COM- POUNDS Bernard L. Zenitz, Colonie, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 24, 1959, Ser. No. 835,405 22 Claims. (Cl. 260292) This application is a continuation-in-part of my prior copending application Serial No. 697,531, filed November 20, 1957, now abandoned.

This invention relates to new monocarbocyclic arylcarbamyl-lower-alkylamines, to salts thereof, and to methods for the preparation thereof.

N [N-(monocarbocyclic .aryl)carbamyl-lower-alkyl] amines and N'-[N-loWer-alkyl-N-(monocarbocyclic aryl) carbamyl-lower-alkyl]amines wherein the amino moiety is dialkylamino or piperidino are known. The invention resides in the concept of the compounds obtained when the known types of N-(monocarbocyclic aryl)carbamyllower-alkyl and N-lower-alkyl-N-(monocarbocyclic aryl) carbamyl-lower-alkyl radicals are attached to the nitrogen atoms of a 1,5-iminocycloalkane or 1,5-iminocycloalkene radical, whereby new and useful compounds are produced.

In the compounds of my invention the monocarbocyclic aryl radicals can be unsubstituted phenyl or phenyl substituted by substituents known in compounds of the lidocaine type having local anesthetic activity, such as loweralkyl, lower-alkoxy or halogen.

In the compounds of my invention the 1,5-iminocycloaliphatic ring has at least seven ring members, preferably seven or eight, and can be unsubstituted or substituted in the 3-position by such known types of radicals as hydroxy, acyloxy, halogen, oxo, carboalkoxy, and the like. In the case where a 1,5-iminocycloalkene radical is present, the ring preferably has the double bond at the 2,3-position of the ring.

A preferred aspect of the invention relates to compounds having the formulas:

wherein R, R' and R represent hydrogen, lower-alkyl, lower-alkoxy or halogen radicals, R' represents hydrogen ice or a lower-alkyl radical, Y represents a lower-alkylene radical, n represents an integer from 1 to 2, and A represents CH CH(OH), 0 0, CHCl, CHBr, CH(O-Acyl), C(OH)(COO-lower-alkyl) or C(OH)(lower-alkyl). The invention also relates to salts of the foregoing.

In the above general Formulas I and II, R, R and R each represents hydrogen, lower-alkyl, lower-alkoxy or halogen radicals and can be the same ordifierent. When R, R and R represent lower-alkyl or lower-alkoxy radicals, they can have from one to about four carbon atoms and can be straight or branched, and thus stand for such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy, and the like. When R, R and R" represent halogen atoms, they stand for any of the four halogens, fluorine, chlorine, bromine or iodine. A particularly preferred class of compounds are those in which R and R represent lower-alkyl radicals and R represents hydrogen.

In the above general Formulas I and II, R' represents hydrogen or a lower-alkyl radical. When R represents a lower-alkyl radical, it can have from one to four carbon atoms and can be straight or branched, and thus stands for such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Z-methylpropyl, and the like.

In the above general Formulas I and II, Y represents a lower-alkylene bridge having from one to about five carbon atoms which can be straight or branched, and thus includes such groups as methylene, ethylene, propylene, l-rnethylethylene, Z-methylethylene, butylene, penty-lene, and the like. A particularly preferred group of compounds are those in which Y has one or two carbon atoms, i.e., when Y is methylene or ethylene.

In the above general Formula I, n is l or 2. When n is 1, the 1,5-iminocycloalkane moiety is a cycloheptane ring, and the whole molecule is a derivative of nortropane. When n is 2, the 1,5-iminocycloalkane moiety is a cyclooctane ring, and the whole molecule is a derivative of granatanine. The numbering systems are in accordance with the standard nomenclature used in The Ring Index (Patterson and Capell, Reinhold Publishing Corp., 1940), and in Chemical Abstracts. In the 1,5-iminocycloalkane or -alkene moiety the parenthetical numbers 8 and 9 are used in the case where n is 2.

In the above general Formula I, A represents, inter alia, a CH(O-Acyl) group. The exact nature of the acyl group is not critical, provided it is a carboxylic acyl group of relatively low molecular weight, less than about 250. A preferred group of acyl radicals includes lower-alkanoyl, such as formyl, acetyl, propionyl, butyryl, isobutyryl,

valeryl, caproyl, and the like; carboxy-lower-alkanoyl, such as hemi-succinyl, hemi-glutaryl, hemi-adipyl, and the like; monocarbocyclic aroyl, such as benzoyl, p-toluyl, pnitrobenzoyl, 3,4-dinitrobenzoyl, p-methoxybenzoyl, 3,4,5- trimethoxybenzoyl, and the like; monocarbocyclic aryllower-alkanoyl, such as phenylacetyl, 2-.phenylpropionyl, l-phenylpropionyl, p -nitrophenylacetyl, and the like; lower-alkanoyl, such as acryloyl, crotonoyl, and the like; monocarbocyclic aryl-lower-alkenoyl, such as cinnamoyl, p-nitrocinnamoyl, phenylcrotonoyl, and the like; and carbamyl, CONRR", wherein R' and R" are hydrogen or loWer-alkyl groups, such as carbamyl, N-methylcarbarnyl, N,N-dimethylcarbamyl, and the like.

The compounds of my invention have pharmacodynamic properties, in particular, local anesthetic activity. For example, 8 [N (1,6 dirnethyIphenyDcarbamYI- methyl]nortropaue as its hydrochloride salt was found .to. be, about 7.5 times as active as procaine hydrochlorideand 1 2.3 times as active as lidocaine hydrochloride when tested by the 'intracutaneous wheal test in guinea pigs [Bulbring and Wajda, J. Pharmacol. & Exptl. Therap. 85, 78 r (1945)]. When tested by the corneal anesthesia method by topical application on the rabbit eye, this compound was found to be about 1.6 times as active as ***e hydrochloride;

The compounds of the invention are prepared by react-.

ing an N-(monocarbocyclic aryl) carbamyl lower alkyl halide or an N-lower-alkyl-N-(monocarbocyclic aryl)- carbamyl-lower-alkyl halide with a 1,5-iminocycloalkane or 1,5-iminocycloalkane. A preferred method comprises heating the reactants at .a temperature between about 50 C. and 150 C. in the presence of an acid-acceptor. The reaction is preferably carried out in an organic solvent, inert under the conditions. of'the reaction, such :as

anhydrous lower-alkanols, benzene, xylene, and the like.

The acid-acceptor neutralizes the hydrogen halide which is split out during the course of the reaction, and is a basic substance which forms water-soluble by-products easily separable from the main product ofthe reaction, including such'substances asalkali metal salts of weak acids, e.g., sodium carbonate, potassium carbonate, sodium acetate, sodium alkoxides, sodium amide, and the like. The acid-acceptor can also be in the form of an excess quantity of 1,5-iminocycloalkane or -alkene, which can be recovered in the form of the hydrohalide salt and The hydroxy compounds can be dehydrated .to introduce a double bond between the 1- and 2-positions of the 1,5-

iminocycloalkane ring, e.g., by heating with mineral acid,

potassium bisulfate, or the like, and the double bond re-. duced to .give compounds unsubstituted in the .3-pos1t1on (A=CH Alternatively thehydroxygroup in the 3- position can be replaced by chlorine or bromine by treating with the thionyl chloride or'thionyl bromide, and the resulting 3-chloro or '3-br'omo compound can then be dehydrohalogenated by heating with a base, such as alkali 1- metal hydroxides or alkoxides or amino compounds, to 4 give the same unsaturated compound obtained by deh dration of the 3-hydroxy compound.

The compounds and intermediates wherein A is C=O 1 are converted to compounds Where A is C(OH) (lower- -alkyl) by a Grignard reaction with a lower-alkyl-lithium. Compounds wherein A is C=O also serves as intermediates for the compounds where A is C(OH)(COO-1oweralkyl); reaction with hydrogen cyanide gives the cyanhydrin [A=C(OH) (CN)] which can then be hydrolyzed ,to the corresponding carboxylic acid and esterified with a lower alkanol.

These changes in the groupA are preferably efiected before the 1,5-iminocycloalkane and N-(monocarbocyclic aryl)carbamyl-lower-alkyl or "N-lower-alkyl N (monocarb o-cyolic aryl)-.carbamyl-lowcr-alky-l moieties are oom-- bined in order to avoid side reactions with the amide linkage. The foregoing is: summarized in the following 'floW-sheet (X is Clor Br) l (base) My N'-[N-(monocarbocyclic 'aryl)carbamyl-lower-al-I kyl]-amines and TN-[N-lower-alkyl N (monocarbocyclic aryl)carbamyl-lower-alkyl] amines are useful in the free base form or in the; form of acid-addition or quaternary ammonium salts, and both forms are within the purview of the invention, and, in fact,"are considered to be one and the: same invention; Th'e=acid-addition and quaternary ammonium salts are simply a more convenient form for use, and inapracticquseof' the salt form inherently amounts to use of the .base form.., Asused in thea pended claims, unless specifically designated, otherwise, the terms N'-[N-(monocarbocyclic aryl) carbamyl-lowere alkyl] 1,5. iminocycloalkane and -imin'ocycloalkene and N'-- [N-loWer-alkyl-N-(monocarbocyclic aryl)car.- bamyl-lower-alkyl] 1,5-iminocycloalkane? and -imino-- cycloalkene? mean ;both the free base form and the acidaddition and-lower-alkyl, lower-alkenyl and monocarbocyclic aryl-lower-alkyl quaternary ammonium salt form of the molecular structure recited. Pharmacologically acceptable salts are .salts whoseanions are innocuous to the animal organism in pharmacological doses of the salts,

so that beneficial physiological properties inherent in ;the V free bases-are not vitiated by side-effects ascribable to the anions; in other words, the latter do not substantially affect the pharmacological propertiesinherent in the cations. Appropriate acids-addition salts are-those derived from mineral acids such as hydrochloric acid, hydrobromic acid,:hydriodic acid, nitric acid, sulfuric acid,,and phosphoric acid; and organic acids such as acetic. acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,'sulfamic acid and quinic acid and naphthalenesulfonic acid. Thequa- I ternary ammonium salts are obtained by the addition of alkyl, alkenyl or aralkyl esters of-in0rganic acids or organic'sulfonic acids to the free base form of the compounds; The :alkyl, alkenyl or aralkyl esters so used include. such'cornpounds as methyl chloride, methyl bro mide, methyl iodidegethylbromide, propyl chloride, 2- hydroxyethyl bromide, allyl chloride, allyl bromide, methyl sulfate, methyl benzenesulfonate', methyl p-toluenesulfonate, benzyl. chloride, benzyl bromide, and substituted benzyl halides, such as p-chlo'robenzyl chloride,

p-nitrobenzyl chloride, o-chlorobenzyl chloride, p-methoxy benzyl chloride, and the like.

The acid-addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.

The quaternary ammonium salts are prepared by mixing the free base and the alkyl, alkenyl or aralkyl ester in an organic solvent. Heating can be used to facilitate the reaction, although salt formation usually takes place readily at room temperature. The quaternary ammonium salt separates directly or can be obtained by concentration of the solution.

An alternative method of preparation of the quaternary ammonium salts comprises direct reaction of an N-(monocarbocyclic aryl)carbamyl-lower-alkyl halide or an N- lower alkyl-N-(monocarbocyclic aryl)carbamyl-loweralkyl halide with an N'-hydrocarbon substituted 1,5-imir1o cycloalkane or -alkene.

Although pharmacologically acceptable salts are preferred, those having toxic anions are also useful. All acid-addition salts are useful as intermediates in purification of the free bases, and toxic acid-addition and quaternary ammonium salts are useful as intermediates in preparing pharmacologically acceptable salts by ion exchange procedures. All crystalline salts are also useful as characterizing derivatives of the free bases.

The structures of the compounds of the invention have been established by chemical analysis and by the processes for their preparation, which can only lead to compounds of the assigned structures.

The following examples will further illustrate the invention, without the latter being limited thereto.

EXAMPLE 1 8 N (2,6 dimethylphenyl)carbamylmethyl]-3-hydroxynortropane [1; R and R are CH R" and R'" are H, Y is CH n is 1, A is CH(OH)].A mixture of 9.9 g. (0.05 mole) of N (2,6 dimethylphenyl)carban1ylmethyl chloride, 7.0 g. (0.055 mole) of nortropine and 5.3 g. (0.05 mole) of powdered anhydrous sodium carbonate in 150 ml. of absolute ethanol was refluxed with stirring for twenty-four hours. Another 2.7 g. of sodium carbonate was then added and the mixture refluxed for twenty-four hours longer. The reaction mixture was filtered, the solid material washed with ethanol, and the combined filtrate and washings were concentrated in vacuo. The residue was dissolved in 400 ml. of hot benzene, and the benzene solution was washed several times with water and then extracted with dilute hydrochloric acid. The acid extracts were made basic with concentrated ammonium hydroxide and the precipitated product was collected by filtration. The product was purified by dissolving it in 250 ml. of hot benzene, concentrating the volume to 125 ml. and allowing the product to crystallize. There was thus obtained 11.9 g. of 8-[N-(2,6-dimethylphenyl)carbamylmethyl] 3 hydroxynortropane, M.P. 177178.5 C. (corr.) after drying over phosphorus pentoxide at 100 C. and 0.1 mm. for four hours.

Analysis.Calcd. for C17H24N2021 C, H, N, 9.72. Found: C, 70.78; H, 8.20; N, 9.67.

The hydrochloride salt of 8-[N-(2,6-dimethylphenyl)- carbamylrnethyl] -3-hydroxynortropane was prepared from a solution of 84 'g. of the free base in isopropyl alcohol solution by addition of an excess of concentrated hydrochloric acid. The salt separated upon cooling the solution, and there was obtained 89 g., M.P. 235-237 C. (corr.).

AnalysiS.Calcd. for C17Hz4N202.HCII N, Cl, 10.92. Found: N, 8.47; Cl, 10.68.

The methiodide salt of 8-[N-(2,6-dimethylphenyl)- carbamylmethyl] -3 -hydroxynortropane was prepared from a solution of 2 g. of the free base and 4 g. of methyl iodide in 75 ml. of acetone. The solution was kept at room temperature for three days, and the product which separated was collected by filtration and washed with acetone, giving 2.4 g. of methiodide. A sample of the methiodide when recrystallized from ethanol and dried over phosphorus pentoxide at C. and 0.2 mm. for four hours had the M.P. 234237 C. (corr.).

Analysis.-Calcd. for C18H27N202I: N, I, 29.50. Found: N, 6.50; I, 29.59.

Pharmacological evaluation of 8-[N-(2,6-dimethylphenyl)carbamylmethyl] 3 hydroxynortropane hydrochloride in aqueous solution administered intradermally in guinea pigs according to the method of Bulbring and Wa'jda [1. Pharmacol. & Exptl. Therap. 85, 78 (1945)] has shown that this compound in terms of its free base is approximately 2.4 times as active a local anesthetic as procaine. 8- [N- (2,6-dimethylphenyl) carbamylmethyl] 3-hydroxynortropane hydrochloride was found to have an acute intravenous toxicity (LD in mice of 24:05 mg./kg.

By replacement in the preceding preparation of the N-(2,6-dimethylphenyl)carbamylmethyl chloride by a molar equivalent amount of N-phenylcarbamylmethyl chloride, N-(Z-methyl 6 chlorophenyl)carbamylmethyl chloride, N-(2,4,6-trimethylphenyl)carbamylmethyl chloride, N-(2,4,6-triisopropylphenyl)carbamylmethyl chloride, or N-(2,6-dimethyl-4-n-butoxyphenyl)car'bamylmethyl chloride (prepared from 2,6 dimethyl-4-n-butoxyaniline and chloroacetyl chloride), there can be obtained, respectively, 8-(N-phenylcarbamylmethyl) 3 hydroxynortropane [1; R, R, R and R are H, Y is CH n is 1, A is CH(OH)]; 8-[N-(2-methyl-6-chlorophenyl)carbamylmethyl]-3-hydroxynortropane [1; R is CH R is Cl, R and R are H, Y is CH n is 1, A is CH(OH)]; 8-[N-(2,4,6-trimethylphenyl)carbamylmethyl] 3 hydroxynortropane [1; R, R and R" are CH R" is H, Y is CH n is 1, A is CH(OH)]; 8-[N-(2,4,6-triisopropylphenyl)carbarnylmethyl] 3 hydroxynortropane [1; R, R and R are CH(CH R is H, Y is CH n is 1, A is CH(OH)]; or 8-[N-(2,6-dimethyl-4-n-butoxyphenyl)carbamylmethyl]-3-hydroxynortropane [1; R and R are CH R is O(CH CH R" is H, Y is CH n is 1, A is CH(OH)].

By replacement in the preceding preparation of the N-(2,6-dimethylphenyl)carbamylmethyl chloride by a molar equivalent amount of 1-methyl-2-[N-(2,6-dimethylphenyl)carbamyl]ethyl chloride (prepared from 2,6-dimethylaniline and ,B-chlorobutyryl chloride) or S-[N- (2,6-dimethylphenyl)carbamyl1pentyl chloride (prepared from 2,6-dimethylaniline and e-chlorocaproyl chloride), there can be obtained, respectively 8-{1-methyl-2-[N- (2,6-dimethylphenyl)canbamyl]ethyl} 3 hydroxynortropane [1; R and R are CH R and R are H, Y is CH CH(CH n is 1, A is CH(OH)]; or 8-{5-[N-(2,6- dimethylphenyl)carbamyl]pentyl} 3 hydroxynortropane [1; R and R are CH R and R are H, Y is (CH n is l, A is CH(OH)].

By replacement in the preceding preparation of the nortropine by a molar equivalent amount of 3-granataninol there can be obtained 9-[N-(2,6-dimethylphenyl) carbamylmethyl]-3-hydroxygranatanine [1; R and R are CH R" and R" are H, Y is CH n is 2, A is CH(OH)].

By replacement in the preceding preparation of the nortropine by a molar equivalent amount of 3-nortropanone, 3-chloronortropane (from nortropine and thionyl chloride), 3-bromonortropane (from nortropine and thionyl bromide), 3-benzoyloxynortropane (from nortropine and benzoyl chloride), or 3-hydroxy-3-methylnortropane (from 3-nortropanone and methyllithium), there can be obtained, respectively, 8-[N-(2,6-dimethylphenyl) carbamylmethyl]-3-oxonortropane [1; R and R are CH R and R" are H, Y is CH n is 1, A is C=O]; 8-[N- (2,6-dimethylphenyl)carbamylmethyl] 3 chloronortropane [1; R and R are CH ,'R and R' are H, Y is .moved by filtration and washed with benzene.

bine'd benzene filtrate and washings were washed with.

CH n is 1, A is CHCl]; 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-bromonortropane [LR and Rare CH R" and R are H, Y is CH n is 1, A is CHBr]; 8-[N- (2,6-dimethylphenyl)carbamylmethyl] 3 benzoyloxynortropane [1; R and R are CH R" and R are H, Y is CH n-is 1,-A is CH(OCOC H )];;or 8-[N-(2,6- dimethylphenyl)carbamylmethyl] 3 hydroxy-3-methylnortropane [1; R and R areCH R and R are H, Y is CH n is LA is C(OH)(CH 8-[N-(2,6-dimethylphenyl)carbamylmethyl] 3 hydroxynortropane. can be reacted with hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, acetic acid, quinic acid, Z-naphthalenesulfonic acid, phosphoric: acid, methyl iodide, methyl bromide, ethyl bromide, allyl bromide, benzyl chloride, .o-chlorobenzyl chloride, methyl p-toluenesulfonate, or methyl sulfate, to give, respectively, the hydrochloride, hydrobromide, hydriodide, sulfate, or bisulfate, acetate, quinate, Z-naphthalenesulfonate, phosphate or acid phosphate, methiodide, methobromide; etho-.

bromide, allobromide, benzochloride, o-chlorobenzochloride, metho-p-toluenesu1fonate, or methosulfate. salt.

EXAMPLE 2 8 [N (2,6 dimethylphenyl)carbamylmethyl] nortropane [I;F=R and R are CH .R", and R are H, Y is CH n is 1, A is CH ].-A mixture of 5.9 g. (0.030 mole) of N-(2,6-dimethylphenyl)carbamylmethyl chloride and i 7.0 g. (0.063 mole) of nortropane in 150 ml. of dry benzene was refluxed for eight hours. After the. T636. tion mixture had been allowed to stand overnightythe white precipitate of nortropane. hydrochloride was re-.

two 50 ml. portions of water and extracted with dilute hydrochloric acid (4 ml. of concentrated hydrochloric acidin 50 ml. of water),-and washed with water until neutral. made basic with ammonium hydroxide.

a volume of 300ml. There was thus obtained 7.2 g..of 8-[N-(2,-6 dimethylphenyl) carbamylmethylJnortropane which was recrystallized from 350 ml. of hexane. and dried.

over phosphorus pentoxide at 80 C. and 0.2 mm. for six hours, giving a sample having the M.P. 154-155 C. (corn).

Analysis.-Calcd. for CHI-124N202 N (total), 10.29;

N (basic), 5.14. Found: N (total), 10.25; N (basic), 5.11.

The hydrochloride salt of 8-[N-(2,6-dimethylphenyl)- carbamylmethyHnortropane was prepared from a solution ,of 39 g. of the free base in :200 ml. of isopropyl alcohol and 12.2 ml. of concentrated hydrochloric acid. Thetsolution was: filtered while hot'and then cooled ,to 5 C. whereupon the product'separated. The salt was collected by filtration, washed with cold isopropyl alcohol and dry ether, and dried at 70 C. for twenty hours, giving 40.5

pigs according to the method of Bulbring and Wajda, 10c. .cit., has shown that this compound in terms of its freev base is approximately 7.5 times as active a local anesthetic as procaine, and 2.3 times as activeas lidocaine. '8-[N-' (2,6-dimethylphenyl) carbamylmethylJnortropane hydrochloride was found to have an acute intravenous toxicity (LD in mice of.10.5 10.9 mg./kg.

EXAMPLE 3 I 8 [N (2,6.-dimethylphenyl)carbamylmethyl]nortropidz'ne [II; R and R are CH R" and R' areH, YiS CH n is .1] was prepared from 5.9 g. (0.030molc). of

The com-.

The acid extracts were combined, filtered, and The product was collected by filtration, dissolved in 700 m1.- of hot: hexane and the solution was filtered and concentrated to.

8? N-(2,6,-dimethylphenyl)carbamylmethyl chloride and-6.9

g. (0.063 mole) of nortropidine in 150 m1. of dry benzene I to' have an acute intravenous toxicity. (LD in mice of 13:12 m g/kg.

EXAMPLEM 8 [N (2,6-dimethylphenyl)carbamylmelhyflpseudo- 3-hydr0xyn0rtropane [1; R andR'. are CH R and R- are H, Y is CH n is 1, A is CH(OH)].-A mixture of 5.9. g. (0.030 mole) of N-(2, 6-dimethylphenyl)carbamyl= methyl. chloride, 8.0g. (0.063 mole) of pseudo-nortro-- pine in 100 ml. of absolute ethanol was refluxed for eight hours. The reaction mixture was allowed to stand overnight and .then.was concentrated in vacuo. was refluxed for several minutes" with-IOO-mhfiof chloroform, .cooled, and the insoluble pseudo-nortropinehydrochloride ;was*removed :by filtration and i'washed with chloroform. The combined chloroform filtrate and washings were washed with three'25 ml. portions of water,

extracted with dilute hydrochloric acid (5 ml; of con centrated hydrochloric acid .in v50 ml. of water), and i The: combinedacid extracts and washings were filtered and. .made basic with: concentrated: ammonium hydroxide. The product whichseparated was collected and1dissolved finally washed with four10 ml. portions of water.

in 200 fill-:Of benzene, and the solution was. filtered, concentrated to ml. and. diluted with 30 m1..of hexane.

There was thus obtained 7.1 g. of 8-[N(2,6-dimethylphenyl)carbamylmethyhpseudo 3 hydroxynortropanem which was further purified by recrystallization successively from benzene-hexane, ethyl acetate-hexane and ethyl acetate, and dried over phosphorus pentoxidei atroom temperature and 0.1 mm. for twenty-four hours to give a sample with the M.P. 176.5-1785 C. (corn). A mixed melting point with the S-EN-(2,6-dimethylphenyl)car bamylmethyl]-3-hydroxynortropane obtained inExample 1 showed a depression to 149160 C.

Analysis.Calcd. ffor ci namo N (total), 9.72; N, (basic), 4.86. Found: N (total), 9.52; N (basic),.4.82.

Pharmacological evaluation of 8-[N-(2,6 -dimethyl phenyl)carbamylmethyl]pseudo-3-hydroxynortropane in anaqueous solution of its acid-addition salt'administered intradermally in guinea pigs accordingto the method of Bulbring and Wajda, loc.- cit.., has shown thatthis com-- 1 pound in .terms of its free base is approximately 0.9 times; as: active a local anesthetic as procain'e.. 8-[Nj-(2,6-di-- methylphenyl)carbamylmethyl] pseudo 3 I- hydroxynop' tropanewas found tov have an acuteintravenous toxicity )in mice of 581-4.8 mg./kg.

droxynortropane [1; R and R. are CH RT and R"! are H, Y-is CH CH n is 1, A is.CH(-OH)].A'rnixture of 12.7 g. (0.060 mole) of 2-IN-(2,6-dimethylphenyl)care bamy1]ethy1'ch1oride,:8.0 g. (0.063 mole) of nortropine and 6.4 g; (0.06 mole) of anhydrous sodium carbonate in 200 ml. of absolute ethanol was refluxed for twenty hours. The inorganic solids .were removed by filtration,

The residue washed with ethanol, and the combined ethanol filtrate and washings were concentrated in vacuo. The residue was dissolved in 200 ml. of dilute acetic acid, the solution filtered through filter cel, and then made basic with solid potassium carbonate. The mother liquors were decanted from the resulting gum which was then washed with water and dissolved in chloroform. The chloroform solution was washed with 50 ml. of water, filtered, and concentrated in vacuo. The resulting pale yellow oil was dissolved in 150 ml. of boiling benzene, and the solution was filtered and concentrated to 75 ml. and diluted with 35 ml. of hexane, giving 10.6 g. of crystalline product, M.P. 117119 C. The latter was recrystallized twice from a benzene-hexane mixture and then twice from ethyl acetate and dried over phosphorus pentoxide at 100 C. and 0.05 mm. -for five hours giving 8-{2- [N-(2,6-dimethylphenyl) carb amyl] ethyl}-3ahydroxynortropane, M.P. 151-153" C. (corn).

Analysis.-Calcd. for C H N O N (total), 9.27; N (basic), 4.63. Found: N (total), 9.06; N (basic), 4.6 2.

Pharmacological evaluation of 8-{2-[ N (2,6-dimethylphenyl)carbamyl]ethyl}-3-hydroxynortropane in an aqueous solution of its acid-addition salt administered intradermally in guinea pigs according to the method of Bulbring and Wajda, loc. cit., has shown that this compound in terms of its free base is approximately 1.2 times as active a local anesthetic as procaine. 8-{2-[N- (2,6 dimethylphenyl)carbamyl]ethvl}-3-hydroxynortropane was found to have an acute intravenous toxicity (LD in mice of 6810.4 trig/kg.

EXAMPLE 6 8 {2-[N-(2,6-dimethylphenyl)carbamyl]ethyl}n0rtr0- pane [1; R and R are CH R and R are H, Y is OH CH n is 1, A is CH was prepared from 8.5 g. (0.040 mole of N-(2,6-dimethylphenyl)carbamylethyl chloride, 4.7 g. (0.042 mole) of nortropane and 4.2 g. (0.04 mole) of sodium carbonate in 200 ml. of absolute ethanol according to the manipulative procedure described above in Example 5. There was thus obtained 9.9 g. of 8 {2 [N-(2,6-dimethylphenyl)carb-amyl]ethyl}nortropane, M.P. 119-122 C. (corr.) when recrystallized from hexane.

Analysis.-Calcd. for C H N O: N (total), 9.78; N (basic), 4.89. Found: N (total), 9.73; N (basic), 4.85.

Pharmacological evaluation of 8-{2-[N-(2,6-dimethylphenyl)carbamyl]ethyl}nortropane in an aqueous solution of its acid-addition salt administered intradermally in guinea pigs according to the method of Bulbring and Wajda, loc. cit., has shown that this compound in terms of its free base is approximately 4 times as active at local anesthetic as procaine. 8-{2-[N-(2,6-dimethylphenyl) carbamyl]ethyl}nortropane was found to have an acute intravenous toxicity (LD in mice of 8.6 $0. 6 mgkg.

EXAMPLE 7 8-[N-(2,6-dimethylphenyl) carbamylmethyl] -3-acet0xy nortropane [1; R and R are CH R and R are H, Y is CH n is 1, A is CHOCOCH ].A mixture of 4 g. of 8 [N (2,6-dimethylphenyl)carbamylmethyl]-3-hydroxynortropane (prepared as described above in Example 1) and 4 ml. of acetic anhydride in 20 ml. of pyridine was allowed to stand at room temperature overnight. The reaction mixture was then heated on a steam bath for two hours and concentrated in vacuo. The residue was dissolved in 25 ml. of absolute ethanol and the solution again concentrated in vacuo. The residue was dissolved in 200 ml. of dilute acetic acid, and the solution filtered through filter cel and then made basic with potassium carbonate. The mixture was cooled and the product collected by filtration and recrystallized from hexane, giving 4.1 g., M.P. l29l31 C. The latter was recrystallized from a mixture of 25 ml. of benzene and 50 ml. of hexane, and dried over phosphorus pentoxide 10 at C. and 0.3 for eight hours, giving 3.9 g. of 8- [N-(2-6-dimethylphenyl) carb amylmethyl] -3-acetoxynortropane, M.P. l42.5-144.5 C. (corn).

Analysis.-Calcd. for C19H26N203: C, H, N, 8.48. Found: C, 68.90; H, 8.07; N, 8.32.

Pharmacological evaluation of 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-acetoxynortropane in an aqueous solution of its acid-addition salt administered intraderm'ally in guinea pigs according to the method of Bulbring and Wajda, loc. cit., has shown that this compound in terms of its free base is approximately equally as active a local anesthetic as procaine. 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3 acetoxynortropane was found to have an acute intravenous toxicity (LD in mice of 30:1.6 mg./kg.

By replacement in the preceding preparation of the acetic anhydride by a molar equivalent amount of cinnamoyl chloride, 3,4,5-trimethoxyben zoyl chloride, N,N- dimethylcarb'almyl chloride, hexanoyl chloride, succinic anhydride, or phenylacetyl chloride, there can be obtained, respectively, 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-cinnamoyloxynortropane [1; R and R are CH R and R are H, Y is CH n is 1, A is CHOCOCH CHC H J 8 [N (2,6-dimethylphenyl)carbamylmethyl]-3-trimethoxybenzoylnortropane [I; R and R are CH R and R are H, Y is CH n is 1, A is CH0COC H (OCH 8 [-N-(2,6-dimetlhylphenyl)carbamylmethyl]-3-dimethylcarbamyloxynortropane [I; R and R are CH R and R are H, Y is CH n is 1, A is OH-OCO N(CH 8 [N-(2, 6-di=methylphenyl)carbarnylmethyl]3-hexanoyloxynortropane [I; R and R are CH R and R are H, Y is 0H n is 1, A is CHOCO(OH OH3]; 8-[N- (2,6 dimethylphenyl)carbamylmethyl]-3-(B-carboxypropionyloxy)nortropane [1; R and R are CH R and R are H, Y is CH n is 1, A is CHOCOCH CH COOH]; 8 [N (2,6-dimethylphenyl)carbamylmethyl]-3-phenylacetoxynortropane I; R and R are CH R and R are H, Y is 0H n is 1, A is CHOCOCH C H EXAMPLE 8 8 [N-(2,6-dimethylphenyl)carbamylmethyl]-3-pr0pi0- nyloxynortropane I; R and- R are CH R and R' are H, Y is CH n is 1, A is CHOCOC H was prepared from 5 g. of 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-hydroxynortropane and 5 g. of propionic anhydride in 25 ml. of pyridine according to the manipulative procedure described above in Example 7. This compound had the M.P. 143144 C. (c'orr.) when recrystallized from a benzene-hexane mixture.

Analysis.Calcd. for CZdHggNgOgi C, 69.74; H, 8.19; N, 8.14. Found: C, 69.84; H, 8.02; N, 7.91.

EXAMPLE 9 8 {2 [N (2,6-dimethylphenyl)carbamyl]ethyl}-3- acetoxynortropane [I; R and R are CH R" and R are H, Y is OH CH n is 1, A is CHOOOCH was prepared from 4 g. of 8-{2-[N-(2, 6-di'methylphenyl)carbamyl]ethyl}-3-hydroxynortropane and 4 ml. of acetic anhydride in 20 ml. of pyridine according to the manipulative procedure described above in Example 7. This compound had the M.P. 119123 C. (corn) when recrystallized from a benzene-hexane mixture.

Analysis.Calcd. for C H N O C, 69.74; H, 8.19; N, 8.14. Found: C, 69.43; H, 8.46; N, 7.91.

Pharmacological evaluation of 8-{2-[N-(2,6-=dimethylphenyl) carbamyflethyl} 3 acetoxynontropane in an aqueous solution of its acid-addition salt administered intradermally in guinea pigs according to the method of Bulbring and Wajda, loc. cit., has shown that this compound in terms of its free base is approximately 1.3 times as active a local anesthetic as procaine.

'1 1 EXAMPLE i 8 [N-(2,6-dimethylphe'nyl)carbamylmethyl]-3-propionyloxynortropane [1; R and R are CH R" and R are H, Y is CH CH n is '1, A is CHOCOC H was prepared from 5 g. of 8-[N-(2,6-dimethylphenyl)-carbamylmethyl] 3-hydroxynortr0pane and 5 g. of propionic anhydride in ml. of pyridine according to the manipulative procedure described above in Example 7. There was thus obtained propionyloxynortropane, MJP. 1094111 C. (corn) when recrystallized from hexane.

Analysis.-Calcd. for C H N O C, 70.35; H, 8.44;

N, 7.82 O, 13.39. Found: C, 70.58; H, 8.39; N,-7.63;-

.. EXAMPLE 11 (a) Nor-u-ecgonine methyl ester.-Northropinone hydrochlori-de (48.5 g, 0.30 mole) was added portionwise over a period of fifteen minutes to. a solution of 21.5 g..

(0.33 mole) of potassium cyanide in 75 ml. of water.

The solid cyanhydrin which had separated was collected by filtration, washed with pyridine and dried over phosphorus pentoxide; Thecyanhydnin (56 g.) was added.

solved in about 100 ml. of water, decolo'rized with acti-' 'vated charcoal, and the solution was treated with;solid potassiumcarbonate until a white solid separated. The

mixture was extracted with three 100 ml. portions of'chloreform, and the chloroform solution was dried over .anhydrous calcium sulfate and concentrated, .giving 22. 8 g. of solid product. The aqueous layer was further saturated with potassium carbonate, and the solid which 'sepa-. rated was collected and washed with three 150 ml. portions ofchloroform. The chloroform washes were used to extract the aqueous filtrate, then dried andconcentrated, giving an additional 5.5 .g. of solid product. The combined solid product was recrystallized from 200 m1. of ethyl acetate, giving 15.6 g. of nor-m-ecg-onine methyl ester, M.P. 143-145 C.

(b) 8 [N (2,6-dimethylphenyl)carbamylmethyl]-3- hydr0xy-3-carb0methoxynortropane [I; R and R are OH;;, R" and R.' are H, Y is CH n is 1, A is C(OH)@(OOO-CH A mixture of 5.7 g. (0.030 mole) of N-(2,6-dimethylphenyDcarbamylmethyl chloride, 5.6 g. (0.030 mole) of The residue was washed with acetone and the.

nor-wecgonine methyl ester and 3.5 g. (0.033 mole) of EXAMPLE 12 '(a) Nortropi none ethylene glycol ketal.A mixture. of 48.5 g. (0.30 mole) of nortropinone hydrochloride, 90 ml.

(1.5 moles) of ethylene glycol and 1 g. of p-toluenesulionic acid monohydrate in 500 ml. ofdry benzenewas retfluxed tor nineteen hours under a water separator.

Th e' excess benzene and ethylene glycol were then removed in vacuo on a steam bath. The residue was stirred with ditional 11.9, g. of solid product.

product were combined and stirred with 75 ml. of satu-, rated potassium carbonate solution; chloroform was 1 added, the mixture was stirred and the chloroform solu- 12 1 about 400 ml. ofdry acetone and filtered, giving 41.9 g. of. solid product. The filtrate was concentrated in vacuo. to remove the acetone and additional ethylene glycol, and the residue was agam treated with acetone to give anadtion-separated. The aqueous mixture was filtered to .remove inonganic salts which were washed with chloroform, and the combined chloroform extractsv and washings were filtered through anhydrous calcium sulfate and concen- The residue was distilledthrough aa tratedin vacuo. Vigreuxcolumn, and the fraction boiling at,68-69. C.

(0.7-0.8 mm.) was collected and redistilled, giving 34.2 g. of'nortropinone ethylene glycol ketal, B.P. 70 C. (0.8 5.

(b) 8 [N (2,6-dimethylphenyl)carbamylmethyl] nortropinone ethylene glycol ketal was prepared from 7.9 g. (0.040? mole) v of N'-(*2,6-dimethylphenyl)carb-amyla methyl chloride, 7.4 g.: (0.044 mole) of nortropinone ethylene glycol ketalan-d 6.4 g. of anhydrous sodium car-7.

bonate in 200 ml. of, absolute; ethanol according to the col ketal, 'M.P. 1267129" C.

Analysis-Calm. :for C H gN O3: C, 69.06; H, 7.94;

N, 8.48. Foundz C, 69.33; H,%8.08;'N,' 8.46.

(c) 8.- [N (2,6-dimethylphenyl)carbamylmethyl] nortropinone [-I; R and R-'are CH Rf and .R"! are H, Y is CH n is 1, A is C=O]:-A mixture of 2.4 g. of 8-.[N-

(2,6- dimethylphenyl)! L- carbamylmethyl]nortropinone ethylene glycol ketal, 2 ml. of concentratedhydrochloric acid and .15 ml. of waterwas kept at room temperature for about seventy hours The reaction mixture was made basic vwith'saturatedpotassium carbonate, and the solid material which separated was collected byfiltration and dissolved in chloroform. The chloroform solution was. (filtered through anhydrous, calcium sulfate and ;concen-= trated in vacuo. The: residue was dissolved in .50 ml. of

boiling benzene, andthe solution.was filtered, concentrated to 25 ml. and diluted with ml. of hexane; The solution was cooled,,and the resulting product which separated was collected by :filtration, recrystallized from 25 ml. Otf benzene and 75 m1. of hexane and dried over phos-' phorus pentoxide at C. and 0.2 mm. for six hours,-

giving' 1.6 g. of 8-[N-( 2,6.-dimethylphenyl)oarbamyl. methyl[nortropinone,- M-.P.'204-205 C. (corn).

Analysis.Calcd. forC H N O C',7l.29; H, 7.74; N, 9.78. Found: C, 71.22; H, 8.05; N, 9.72. r

The oxime of 8-.[N-(2,6,-dimethylphenyl) car-bamylmethyl1nortropinone :was prepared by heating-4.3 g. of the ketone, 4 g. irof'hydroxylamine hydrochloride, 12 ml. of pyridine and 100 ml. of absolute ethanol at 100 C. until a clear solution resulted- The reaction mixture was kept overnight at roomtemperature, refluxed'one hour,- and then concentrated in vacuo.. The residue was crystal: lized from water, giving 3.8 g. ofthe .oxime which had the MP. 1985-201 C.I(corr.) when recrystallized from acetone- Analysis.'Calcd. for-C H N' O C, 67.74; H, 7.69; N, 13.94. Found: C; 67.50; H, 7.5.6;'N, 13.87

EXAMPLE l3 8- [N-ethyl-N v- (2,6-dimethylphenyl)carbamylmethyl]- 3u-hydroxyrnortropane [I; R and R areCH ,;R'? is H, Ri'. is CgH Y is CH n is 1, A is CH(OH)].A solu-. tion of 14g. of chloroacetyl chloride in 50 m1. of dry benzene was added dropwise over a one hourperiodto a l stirred solution of N-ethyl-2,6-dimethylaniline (14.9 g., 0.1 mole) in 100 ml. of dry benzene while maintaining The two crops of's-olid the temperature at 18 to 28 C. The mixture was then warmed on a steam bath for about two and a half hours, cooled and diluted to 300 ml. with benzene. The solution was extracted once with dilute hydrochloric acid, three times with water and twice with saturated sodium bicarbonate solution. The organic layer was dried, filtered, and taken to dryness in vacuo. The residual oil was taken into hot hexane, charcoaled and filtered. On cooling, the product separated as large crystals which were collected and dried giving N-ethyl-N-(2,6-dimethylphenyl)carbamylmethyl chloride, M.P. 4143 C. (uncorn).

Analysis.-Calcd. for C H NCIO: N, 6.22. Found: N, 6.22.

The N-ethyl-N (2,6-dimethy1phenyl)carbamylmethyl chloride (6.76 g., 0.03 mole) and nortropine (8.01 g., 0.063 mole) in 250 ml. of acetonitrile were refluxed for about 18 hours. The reaction mixture was worked up according to the procedure described above in Example 2. There was thus obtained 3.76 g. of 8-[N-ethyl-N-(2,6- dimethylphenyl)carbamylmethyl] 3a hydroxynortropane, M.P. 95.298.4 C. (corr.).

Ananlysis.-Calcd. for C H N O N (basic), 4.43; N

(total), 8.86. Found: N (basic), 4.41; N (total), 8.87.

By replacement in the preceding preparation of the N- ethyl-N-(2,6-dimethylphenyl)carbamylmethyl chloride by a molar equivalent amount of 2-[N-ethyl-N-(2,6-dimethyl-4-isopropylphenyl)-carbamyl]ethyl chloride, N-butyl- N-(2-chloro-6-methylphenyl) carbamylmethyl chloride, or N-isopropyl N (2,6-dirnethylphenyl)carbamylmethyl chloride, there can be obtained, respectively, 84 2-[N- ethyl-N-(2,6-dimethyl 4 isopropylphenyl)carbamyl] ethyl}-3-hydroxynortropa11e [1; R and R are CH R" is CH(CH R' is C H Y is CH CH n is 1, A is CH(OH); 8-[N-butyl N (2-chloro-6-rnethylphenyl)- carbamylmethyl] -'3-hydroxynortropane [1; R is CH R is Cl, R" is H, R is C H Y is CH n is 1, A is CH(OH) or 8- [N-isopropyl-N- (2,6-dimethylphenyl) carbarnylmethyl]-3-hydroxynortropane [I; R and R are CH R is H, R' is CH(CH Y is CH n is 1', A is CH(OH)].

By replacement in the preceding preparation of the nortropane by a molar equivalent amount of 3-nortropanone, 3-chloronortropane (from nortropine and thionyl chloride), 3-bromonortropane (from nortropine and thionyl bromide), 3-benzoyloxynortropane (from nortropane and benzoyl chloride), 3-hydroxy-3-methylnortropane, nortropane, nortropidine or S-granataninol, there can be obtained, respectively, 8-[N-ethyl-N-(2,6-dimeth ylphenyl)-carbamylmethyl]-3-oxonortropane [I; R and .R' are CH R is H, R is C H Y is CH n is 1, A is C=O]; S-[N-ethyl N (2,6-dimethylphenyl)carbarnylmethyl] 3-chloronortropane [1; R and R are CH R Y is CH m is 1, A is CHCl]; S-[N- ethyl-N-(2,6 dimethylphenyl) carbamylmethyl1-3-bromonortropane [I; R and R are CH R is H, R is C H Y is CH n is 1, A is CHBr]; 8-[N-ethyl-N-(2,6-dimethyl-phenyl) carbamylmethyl] 3-benzoyloxynortropane [I; R and R are CH R is H, R is C H Y is CH n is 1, A is CH(OCOC H 8-[N-ethyl-N-(2,6-dimethylphenyl)carbamylmethyl]-3-hydroxy 3-methylnortropane [I; R and R are CH R is H, R is C H Y is CH n is 1, A is C(CH )(OH)]; 8-[N-ethyl-N-(2,6-dimethylphenyl)carbamylmethyl]nortropane [1; R and R are CH R is H, R is C H Y is CH n is 1, A is CH 8 [N ethyl-N-(2,6-dimethylphenyl)carbamylmethyl]nortropidine [II; R and R are CH R is H, R is C H Y is CH n is 1]; 9-[N-ethyl-N-(2,6-dimethylphenyl)carbamylmethyl] 3 hydroxygranatanine [1; R and R are CH R is H, R is C H Y is CH n is 2, A is CH(OH)].

EXAMPLE 14 8-[N-pr0pyl N (2,6 dimethylphenyl)carbamylmethyl]-3-hydroxynortropane [1; R and R are CH R is H, R is (CH CH Y is CH n is 1, A is CHOH].-

14 N-propyl-Z,6-dimethylaniline (16.3 g., 0.1 mole) in 150 ml. of dry benzene was treated with a solution of 15.0 g. (0.13 mole) of chloroacetyl chloride in 600 ml. of dry benzene according to the manipulative procedure described above in Example 13. The product was recrystallized from hexane giving 20.1 g. of N-propyl-N-(2,6- dimethylphenyl)carbamylmethyl chloride, M.P. 5960 C. (uncorr.).

Analysis.Calcd. for C H NClO: N, 5.84; Cl, 14.80. Found: N, 5.92; Cl, 15.00.

N-propyl N (2,6-dirnethylphenyl)carbamylmethyl chloride (7.19 g., 0.03 mole) and 8.01 g. (0.063 mole) of nortropine in 250 ml. of acetonitrile were reacted according to the manipulative procedure described above in Example 2. The product was isolated in the form of the free base and recrystallized from dry benzene giving 4.56 g. of 8- [N-propyl-N- (2,6-dimethylphenyl) carbamylmethyl1- 3-hydroxynortropane, M.P. 1l9.6-121.0 C. (corr.).

Analysis.Calcd. for C2oH3 N2O2: N (total), 8.49; N (basic), 4.25. Found: N (total), 8.39; N (basic), 4.17.

EXAMPLE 15 1-{ 8-[N methyl N-(2,6-dimethylphenyl)carbamyl] ethyl}-3-hydr0xynortropane hydrochloride [I; R, R and R are CH R is H, Y is CHCH n is 1, A is CHOH].--A solution of 26.0 g. (0.12 mole) of ozbromopropionyl bromide in 60 ml. of dry benzene was added dropwise with stirring and cooling to a solution of 13.5 g. (0.10 mole) of N-methyl-2,6-dimethylaniline in 120 ml. of dry benzene according to the manipulative procedure described above in Example 13. The product was recrystallized from hexane giving 17.1 g. of l-[N- methyl-N (2,6-dirnethylphenyl)carbamylethyl1bromide, M.P. 80.5 C. (uncorr.).

Analysis.-Calcd. for C H BrNOz C, 53.34; H, 5.97; Br, 29.6. Found: C, 53.29; H, 5.77; Br, 29.4.

The 1-[N-methyl-N-(2,6 dimethylphenyl)carbamylethyl]-bromide (8.1 g., 0.03 mole), nortropirie (4.2 g., 0.033 mole) and sodium bicarbonate (7.5 g., 0.09 mole) in ml. of acetonitrile were refluxed for 72 hours. The reaction mixture was worked up according to the procedure described above in Example 1. The product was isolated in the form of the hydrochloride salt and recrystallized from an isopropanol-acetone mixture giving 1.3 g. of 1% S-[N-methyl N-(2,6-dimethylphenyl) carbamyuethyl} 3 hydroxynortropane hydrochloride, M. P. 250.0-2512" C. (dec.) (corr.).

Analysis.-Calcd. for C H N O -HC1: C, 64.66; H, 8.28; N, 7.94. Found: C, 64.88; H, 8.54; N, 7.91.

EXAMPLE l6 8- [N-methyl N-(2,6-dimethylphenyl)carbamylmethyl] nortropane [1; R, R and R are CH R is H, Y is CH n is 1, A is CH ].N-methyl-2,6-dimethylaniline (9.6 g., 0.064 mole) was treated with 15 ml. of chloroacetyl chloride in dry toluene according to the manipulative procedure described above in Example 13. The product was recrystallized from pentane giving 10.8 g. of N-methyl-N-(2,6 dimethylphenyl)carbamylmethyl chloride, M.P. 4143 C. (uncorr.).

N-methyl-N- (2,6-dimethylphenyl carbamylmethyl chloride (6.35 g., 0.03 mole) was treated with 7.01 g. (0.063 mole) of nortropane in 250 ml. of acetonitrile according to the manipulative procedure described above in Example 2. The product was isolated as the free base and recrystallized from hexane giving 4.08 g. of S-[N-methyl- N-(2,6-dimethylphenyl) carbamylmethyl]nortropane, M.P. 82.6-86.6 C. (corr.).

Analysis.Calcd. for C H N O: C, 75.50; H, 9.15; N,

9.78. Found: C, 76.46; 'H, 9.25; N, 9.85.

of its free base is approximately as active as a local anesthetic as procaine.

EXAMPLE 17 8 [N ethyl N (2,6 dimethylphenyl)carbamylmethyl]nrtr0pane [I; R and R are CH R" is H, R is C H Y is CH n is 1, A is CH ].N-ethyl-N-(2,6,-di methylphenyl)carbamylmethyl chloride (6.76 g., 0.03 mole) was reacted with 7.01 g. (0.063 mole) of nortropane in 250 ml. ofacetonitrile according to the manipulative procedure described above in Example 2. The product Was isolated in the form of the free .base and recrystallizedfrom hexane giving 5.10 g. of B-[N-ethyl-N- (2,6-dimethylphenyl)carbamylmethyl]nortropane, M.P.

81.6-83.4 C. -(corr.).

Analysis.Calcd. for C T-1 N 05 N (total), 9.48; N

(basic), 4.66. Found: N (total), 9.48; N. (basic), 4.60.

Pharmacological evaluation of 8-[N-ethyl-N-(2,6-dimethylphenyl)'carbamylmethylJnortropane in an aqueous solution of its acid addition salt administered intradermah ly in guinea pigs according to the method of Bulbring and Wajda, loc. cit., has shown that this compound in terms of its free base is approximately 2.3 times as active a local anesthetic as procaine.

EXAMPLE 18 8 [N propyl N (2,6 dimethylphenyl)carbamylmethyl1nortropane hydrochloride [1; R and R. are CH R is H, R' is (CH CH Y is CH n is 1, A is CH N-propyl N (2,6-dimethylphenyl) carbamylrnethyl chloride (7.19 g., 0.03 mole) was reacted with 7.01 g. (0.063

mole) of nortropane in 260 ml. of acetonitrileaccording to the manipulative procedure described above in Example 2. The product was isolated in the formof its hydro,- chloride salt and recrystallized from an ethanol-ether mixture giving 4.57 g. of 8- [N-propyl-N-(2,6-dimetl1ylphenyl) carbamylmethyl]nortropane. hydrochloride, M.P. 142 .-6-. 143.6 C. (c'orr.).

Analysis.Calcd. for CQ H N Q'HCI: N, 7.98; Cl,

10.10. Found: N, 8.04; Cl, 10.28-

The intermediate N-lower-alkyl-substituted-anilines used in the preparation'of the N-lower-alkyl-N-(monocarbocyclic aryl)carbamyl-lower-alkyl halides are prepared by re-.

ducing the correspondiug N-lower-alkanoyl-substitutedanilineswith an alkali metal aluminum hydride, for ex-' ample, lithium aluminum hydride, in an organic solvent;

N-ethyl-2,6-dimethylaniline, B.P. 9395 C./ 15 mm.,

n 1.5225,v prepared from N-acetyl-2,-6-dimethylaniline. Analysis.Calcd. for C H N: N, 9.38; Found; N,

N-propyl-2,6-dimethy1aniline, B.P. 115.5-118.5 c./24

mm., n 1.5177, prepared from -N propionyl-2,6-dimeth-' 'ylaniline.

Analysis.-Calcd. for C H N: N, 8.57. Found: N,

; Local anesthetic compositions can be formulated using the novel N'-[N-(monocarbocyclic a-ryl)carbamyl-loweralkyl] 1,5-iminocycloa1kanes and -all:enes and their salts disclosed herein together with excipients. By an excipient.

I mean any inert substance used to give the compositions a'suitable form or consistency. In the case of liquid compositions for topical or .injectable administration, the ex-' cipientvis sterile water, optionally containing additional,

compatible ingredients for stabilizing and the like purposes such as methyl para-hydroxybenzoate, chlorobutanol, sodium bisulfite, sodium chloride, dextrose, inositol, etc., 75 C(OH) (COO lower-alkyl), and C(OH) (lower-alkyl);

or containingother pharmacodynamically active ingredients such as a.vasoconstrictor agent,1e.g., epinephrine, phenylephrine; In the case of ointment or cream compositions for topical application, the excipient=is prefer ably petrolatum, optionally containing additionalcompatible ingredients such as lanolin, mineral oil, white wax,

wool fat, etc... Illustrative of suchlocal anesthetic compositions of my invention are thefollowing: an injectable aqueous preparation comprising in reach cubic centimeter 10 mg. of 8- [N-(2,6-dimethylphenyl)carbamylmethyl] nortropane. hydrochloride, 7 mg. ofzsodiumchloride and 1 mg. of methyl para-hydroxybenzoate; an injectafble aqueous preparation comprising inieach cubic centimeter 20 mg. of 8-[N-(2,6-dimethylphenyl)carbamylrnethyflnorr tropane hydrochloride, 0.01 mg. 'of'epinephrine 'hydrochloride, 6 mg. of sodium chloride andl mg. of methyl para-hydroxybenzoate; a topical. aqueous' composition comprising 10. mg. of 8-[N-(2,6-dimethylphenyl)carbam-: ylmethylJnortropane hydrochloride, 4 mg.. of. ChlOIObll-s itanol and enough distilled Water to make 1 ml. of solu tion; an ointment comprising, 1% of 8-'[N-(2,6-'dimethy1-' phenyl)carbamylmethyllnortropane dissolved tin. white petrolaturn.

I claim:

pounds having the formula I (oHiu-oH-om and compounds having theiormula l (GHzh-CHCH where R and R, ,each' are .a member of the group :consistingmof lower-alkyl, lower-alkoxy, and .halogen; ,R" is a member of the group consisting of hydrogen, loweralkyl, lower-alkoxy, and halogen; .R".' is a memberof-the group ,consisting of hydrogen andlower-alkyl, Y is loweralkylene, n is an integer from 1 to 2, and A is'a member of the group consisting of CH OH(OH), C=.O, CHCl, CHBr; 'CHCOAcyI) wherein Acyl -is a carboxylic acyl group conventionally usedin the. tropine alkaloid art and having a molecular weightless than about 250,. C(OH)%v (COO-loWer-alkyl) and .C(OH) (lower-alkyl) e (B) pharmacologically acceptable acid-addition salts thereofland '(C) pharmacologically.acceptable lower-alkyl, lower-- alkeuyl and monocarbocyclic aryl-lower-alkyl. quaternary ammonium salts thereof.

25A memberyof the.group;consisting1of (A) compoundshaving the formula:

" r R OH2$11&H2

and compoundshaving the formula where R7, is a memberof the group consisting of hydro-' 1. A'member of the group. consisting of (A) com-- 17 and (B) pharmacologically acceptable acid-addition salts thereof.

3. A pharmacologically acceptable acid-addition salt of a compound having the formula wherein R and R represent lower-alkyl radicals, Y represents a lower-alkylene radical, and n represents the integer l. v

4. A pharmacologically acceptable acid-addition salt of a compound having the formula wherein R and R represent lower-alkyl radicals, Y represents a lower-alkylene radical, and n represents the integer 2.

5. A pharmacologically acceptable acid-addition salt of a compound having the formula wherein R, R and R' represent lower-alkylradicals, Y represents a lower-alkylene radical, and n represents the integerll.

6. A pharmacologically acceptable acid-addition salt of a compound having the formula wherein R and R represent lower-alky-l radicals, Y represents a lower-alkylene radical, n represents the integer 1, and Acyl represents a carboxylic acyl group conventionally used in the tropine alkaloid art and having a molecular weight less than about 250.

7. A pharmacologically acceptable acid-addition salt of a compound having the formula wherein R and R' represent lower-alkyl radicals, Y represents a lower-alkylene radical, n represents the integer 2, and Acyl represents a car-boxylic acyl group conventionally used in the tropine alkaloid art and having a molecular weight less than about 250.

8. A pharmacologically acceptable acid-addition salt of a compound having the formula wherein R and R represent lower-alkyl radicals, Y represents a lower'alkylene radical, and n represents the integer 1.

t v t 18 9. A pharmacologically acceptable acid-addition salt of a compound having the formula wherein R and R represent lower-alkyl radicals, Y represents a lower-alkylene radical, and n represents the integer 2.

10. Apharmacologically acceptable acid-addition salt of a compound having the formula (CH2) n-OH-Cl-Iz wherein R, R and R represent lower-alkyl radicals, Y represents a lower-alkylene radical, and n represents the integer 1.

11. A pharmacologically acceptable acid-addition salt of a compound having the formula wherein R and R' represent lower-alkyl radicals, Y represents a lower-alkylene radical, and n represents the integer 1.

12. A pharmacologically acceptable acid-addition salt of a compound having the formula wherein R and R represent lower-alkyl radicals, Y represents a loWer-alkylene radical, and n represents the integer 2.

13. A pharmacologically acceptable acid-addition salt of a compound having the formula I @WOMILII wherein R and R represent lower-alkyl radicals, Y represents a lower-alkylene radical, and n represents the integer 1.

14. A pharmacologically acceptable acid-addition salt of a compound having the formula 18. A pharmacologically acceptable acid-addition salt of 8-[N-(2,6 dimethylphenyl)carbamylmethyl] 3 ace- 5 t ttoxynortropane.

19. A pharmacologically' acceptable acid-addition salt of 8- [N (2,6 dimet'hylphenyl)carbamylmethyl] nortropane.

- 20. 8- [N- 2,6-dimethylphe'nyl) car-bamylmethyl] n0rtro-.

pane hydrochloride.

21. A pharmacologically' acceptable acid-addition salt of 8- [N (2,6 dimethylphenyl)carbamylmethyflnortrm pidine.

22. A pharmacologically acceptable acid-addition salt of 8[N'- (2,6 dimethylphenyl)carbamylmcthyl] -no1'-uecgonine methyl ester.

20 R'eferencesCited-by the Examiner, 1

UNITED STATES PATENTS 2,824,106 1 52/1958 Zei'le-et al 260-1292 2,872,452 2/1959 Zeile 26O''292 2,891,064 6/1959 Kundiger- .260-'293 2,921,075 1/1960 Shapiro et a1. 260292 WALTER A. MODANCE, Primary Examiner.

IRVING MARCUSQHERBERT' J. 'LIDOFF, JOHN D;

RANDOLPHgZExuminem.

D. T. 'MCCUTCHENJ. M-. FORD, Assistant Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 3,264,309 August 2, 1966 Bernard Lo Zenitz It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, line 2, for [1, 6-" read M (2,6-

line 16, for "1,S-iminocyc1oa1kane" read 1,5-iminocyc1oalkene column 9, line 37, for "mole" read mole) column 10, line 46, for "CH n read M CH n column 11, line 17, for "Northropinone" read M Nortropinone column 13, line 23, for "Ananlysis" read Analysis D Signed and sealed this 22nd day of August 1967c (SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents

Claims (2)

1. A MEMBER OF THE GROUP CONSISTING OF (A) COMPOUNDS HAVING THE FORMUULA

2. A MEMBER OF THE GROUP CONSISTING OF (A) COMPOUNDS HAVING THE FORMULA: