NO129929B - - Google Patents

Description

Process for the preparation of a monocarbocyclic aryl-carbamyl-alkylamine,

or an acid addition salt or a quaternary ammonium salt thereof.

This invention relates to manufacturing

of new monocarbocyclic arylcarbamyl-lower-alkylamines, resp. salts thereof.

N'-[N-(monocarbocyclic aryl)-carbamyl-lower alkyl]-amines are known in which the amino part is dialkylamino or piperidino. The invention concerns the preparation of compounds which are obtained when the known types of N-(monocarbocyclic aryl)-carbamyl-lower alkyl radicals are connected with the nitrogen atom in a 1,5-iminocycloalkane or 1,5-iminocycloalkene radical

cal, whereby new and useful compounds are produced.

In the compounds produced in

according to the invention, the unsubstituted monocarbocyclic aryl radicals may be unsubstituted phenyl or phenyl substituted with substituents known from lidocaine-type compounds,

who have anesthetic activities, e.g. substituted with lower alkyl, lower alkoxy or halogen.

In the substances produced according to

for the invention, the 1,5-imino-cyclo-aliphatic ring preferably has at least 7 ring members

show 7 or 8, and may be unsubstituted or substituted in the 3-position with such known radical types as hydroxy, acyloxy, halo-

gen, oxo, carboalkoxy and the like. If a 1,5-iminocycloalkene radical is present, the ring preferably contains the double bond in the 2,3-position of the ring.

The compounds produced in

according to the invention has the general formula:

where R, R' and R" represent hydrogen, lower alkyl, lower alkoxy or halogen radicals, Y represents a lower alkylene radical, n an integer that is 1 or 2,

and A represents CH.,, CH(OH), C = O, CHC1, CHBr, CH(O-acyl), C (OH) (COO-lower

II

alkyl), C(OH) (lower alkyl) or CH

(where the double action is linked to the 2-carbon with the elimination of one hydro-

gene so that you get the cycloalkene with the double bond in the 2,3-position of the ring). The invention also includes the preparation of salts of the aforementioned compounds.

In the above general formula, R, R' and R" each represent hydrogen, la-

be alkoxy or halogen radicals, which may be the same or different. If R, R'

and R" represents lower alkyl- or la-

be alkoxy radicals, these can have from 1 to approx. 4 carbon atoms and can be straight or branched, e.g. be groups such as methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, methoxy, ethoxy, propoxy, butoxy and the like. If R, R' and R" represent

re halogen atoms, they denote 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 formula .re-, Y>presents a lower-alkylene-: bridge, having from 1 to about 5 carbon atoms, which can be straight or branched, and thus include such groups as methylene, ethylene, 1-propylene, 1-methylethylene, 2-methylethylene, butylene, pentylene and the like. A particularly preferred group of compounds are those where Y has one or two carbon atoms, i.e. where Y is methylene or ethylene.

In the above general formula, n is equal to 1 or .2. If n equals 1 is 1,5-imino-. the cycloalkane part a cycloheptane ring and the whole molecule is a derivative of nortropane. If n is equal to 2, the 1,5-iminocycloalkane moiety is a cyclooctane ring, and the entire molecule is a derivative of granatanine. The numbering system used is 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 -alkane part, the numbers 8 and 9 given in parentheses are used when n = 2.

In the above general formula, A represents, among other things, the group CH(O-acyl). The exact nature of the acyl groups is not critical, provided it is a carboxylic acid group which has a relatively low molecular weight, below approx. 250. Among the preferred acyl radicals are lower alkanoyl, such as fiormyl, .acetyl, propionyl, butyryl, iso-butyryl, valeryl, caproyl, and the like; car-boxy-lower alkanoyl, such as hemisuccinyl, hemi-glutaryl, hemi-adipyl, and the like; monocarbocyclic aroyl, such as benzoyl, p-toluyl, p-nitrobenzoyl, 3,4-dinitrobenzoyl, p-methoxybenzoyl, 3,4,5-trimethoxybenzoyl, and the like; monocarbocyclic aryl-lower-alkanoyl, such as .phenylacetyl, 2-phenylpropionyl, 1-phenylpropionyl, p-nitrophenylacetyl, and the like; lower-alkenoyl, such as acryloyl, crotonyl, and the like; monocarbocyclic aryl lower alkenoyl, such as cinnamoyl, p-nitrocinnamoyl, phenylcrotonoyl, and the like; and carbamyl, CONR'R", where R' and R" are hydrogen or lower alkyl groups, such as carbamyl, N-methylcarbamyl, N,N-dimethylcarbamyl, and the like.

The compounds produced according to the invention have pharmacodynamic properties, in particular they are effective as local anaesthetics. For example, it was found that 8-[N-(2,6-dimethylphenyl)carbamylmethyl]nortropane in the form of its hydrochloride salt was approximately 7.5 times as active as procaine hydrochloride and 2.3 times as active as lidocaine hydrochloride, when tested by intracutaneous injection in guinea pigs [Bulbring and Wajda, J. Pharmacol. & :Exptl. Therapy. 85, 78 (1945)]. In experiments with corneal anesthesia when applied topically to a rabbit eye, it was found that this compound was approx. 1.6 times as active as cocaine hydrochloride.

According to the invention, the substances are prepared by bringing an N-(monocarbocyclic aryl) carbamyl lower alkyl halide to react with a 1,5-iminocycloalkane or with a 1,5-iminocycloalkane. A preferred method consists in heating the reaction participants to a temperature between 50 and 150° C in the presence of an acid absorber. The reaction is preferably carried out in an organic solvent, which is inert under the reaction conditions, e.g. anhydrous lower alkanols, benzol, xylol and the like. The acid scavenger neutralizes the hydrogen halide that is split off during the reaction, and consists of a basic substance that forms water-soluble by-products, which can be easily separated from the main product of the reaction, e.g. such substances as alkali salts of weak acids, for example sodium bicarbonate, potassium carbonate, sodium acetate, sodium alkaloid, sodium amide, and the like. The acid scavenger can also consist of an excess of 1,5-iminocycloalkane or alkane, which can be recovered in the form of its hydrohalogen salt and used again.

The various groups represented by A in the above general formula I can easily be interchanged. Compounds -which have a hydroxy group in the 1,5-iminocycloalkane ring can be esterified by conventional methods, e.g. e.g. by.heating with a .suitable acid halide or

-anhydride, so one:obtains the corresponding:acyl-oxy compound. 3-hydroxy compounds can also be oxidized to the corresponding oxo compounds, e.g. by means of chromic acid, and ■ conversely, oxo compounds can be reduced to ihydroxy compounds, .f. e.g. by catalytic hydrogenation. The hydroxy compounds can be dehydrated so that a double bond is introduced between the 2- and 3-positions in the 1,5-iminocycloalkane ring, e.g. by heating together with mineral acid, potassium ubisulphate or the like, whereby the double bond is cancelled, so that compounds are obtained which are not substituted in the 3-position (A = CH2). Alternatively, the hydroxy group in the 3-position can be replaced by chlorine or bromine by treatment with thionyl chloride or thionyl bromide, and the resulting 3-chloro or 3-bromo compound can then be de-hydrohalogenated by treatment with

■ .a base, e.g. with alkali hydroxide or ;; alkoxide or with an amino compound, whereby the same unsaturated compound is obtained as obtained by dehydration of the 3-hydroxy compound. The compounds and intermediates in : which A is C = O are converted to for-. bonds in which A is C(OH) (lower alkyl) ...by a Grignard reaction with a lower ; alkyl lithium. Compounds in which A is : C = O also serve as intermediates .;, for compounds in which A is C(OH) (COO-lower alkyl). When reacting with hydrogen- cyanide yields cyanohydrin [A = C(OH) (CN)], which can then be hydrolyzed to the corresponding carbonic acid [A = C(OH) (COOH)] and esterified with a lower alkanol. These changes in group A are preferably carried out before the 1,5-iminocycloalkane and N'-(monocarboxyaryl)carbamyl lower alkyl moieties are combined, in order to avoid side reactions with the amino bond. What has been mentioned above can be summarized as follows (where X denotes Cl or Br):

Acid addition salts or quaternary ammonium salts of compounds having the formula I are water soluble and the compounds are suitably used in this form for physiological use. Pharmacologically usable salts are those whose anions are harmless to the animal organism in pharmacological doses of the salt, so that the good physiological properties found in the free bases are not reduced by side effects that can be attributed to the anions; in other words, the anions do not significantly affect the properties due to the cations. Suitable acid addition salts are those which are obtained with the help of mineral acids such as e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid; as well as organic acids such as acetic acid, citric acid, lactic acid and tartaric acid. The quaternary ammonium salts are obtained by adding alkyl, alkenyl or aralkyl esters of inorganic acids or organic sulphonic acids to the free base. Among the alkyl, alkenyl or aralkyl esters thus applicable are such compounds as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, 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-chlorobenzyl chloride, p-nitrobenzyl chloride, o-chlorobenzyl, 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 corresponding acid and isolating the salt by evaporating the solution, or by allowing the free base and the acid to react with each other in an organic solvent , in which case the salt separates directly, or can be obtained by concentrating 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 easily at room temperature. The quaternary ammonium salt is excreted directly, or can be obtained by concentrating the solution.

An alternative method for producing the quaternary ammonium salts consists in allowing an N-(monocarbocyclic-aryl)carbamyl-lower alkyl halide to react directly with an N-carbon hydrogen-substituted 1,5-iminocycloalkane or -alkene.

Although the pharmacologically acceptable salts are preferred, those that have toc-

sic anions useful. All acid addition salts are useful as intermediates in the purification of the free bases, and toxic acid addition salts and quaternary ammonium salts are useful as intermediates in the preparation of pharmacologically acceptable salts using ion exchange methods. All crystalline salts are also useful as characterizing derivatives of the free bases.

The structure of compounds that are produced according to the invention has been found by chemical analysis and by the fact that the methods that have been used for their production can only lead to compounds that have the stated structures.

The following examples will further illustrate the invention.

Example 1.

8-[ N~( 2, 6- diethylphenyl) carbamylmethyl] - 3- hydroxynortropane

[I;R and R' are CH,,, R" is H, Y is CH„ n is 1, A is CH(OH)].

A mixture of 9.9 g (0.05 mol) N-(2,6-dimethyl-phenyl)carbamylmethyl chloride, 7.0 g (0.055 mol)a nortropine and 5.3 g (0.05 mol) powdered anhydrous sodium carbonate in 150 mL of absolute ethanol was refluxed for 24 hours. Then an additional 2.7 g of sodium carbonate was added and the mixture was refluxed for a further 24 hours. The reaction mixture was filtered, the solid washed with ethanol, and the filtrate plus the washings 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 seed 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 out, giving 11.9 g of 8-[N-(2,6-dimethylphenyl)-carbamylmethyl]-3-hydroxynortropane , melting point 177—178.5° C. (corr.) after drying over phosphorus pentoxide at 100° C. and 0.1 mm for four hours.

Analysis:

Calculated for C, 7H,,4N2O,:C = 70.79; H =

8.39; N = 9,727

Found: C = 70.78; H = 8.20; N = 9.67.

The hydrochloride salt of 8-[N-(2,6-dimethylphenyl)-carbamylmethyl]-3-hydroxy-nortropane was prepared from a solution of 84 g of the free base in isopropyl alcohol by addition of an excess of concentrated hydrochloric acid. The salt separated out on cooling the solution, and 89> g m.p. 235^237° C" (corr.).

Analysis:

Calculated for G17H24<N>20.,. HCl: N = 8.63;

Cl = 10.92.

Found: N'= 8;47; GY= 10.68': The metiodide salt of 8-[[NL('2;6-dimethylphenyl)-carbamyrmethyl]-3-hydroxynortropane was' prepared from a solution of 2 g of the free: base and 4 g methyl iodide in 75 ml of acetone. The solution was kept at room temperature for 3 days, and the precipitated product was filtered off and washed with acetone, whereby got. 2.41 g of metiodide. A sample of the metiodide was recrystallized from ethanol and; dried"- over. f osf brpentoxide at 80° C and; 0;2-; mmi in. 4: hours,. and< then melted at 234-237° C (corr.).

Analysis:

Calculated for C18H27N202J:N = 6.51;

J = 29;50.

Found.: N. - 6.50; J — 29;59.

Pharmacological: assessment, of 8-[N-(2,6r dimethylphenyl.) carbamylmethyl]-3-hydroxy-synortropin-hydrochloride" in aqueous: solution, used: in tracutant. on- guinea pig after it. a-v Bulbring. and Wajdåi specified method [TJ'. Eharmacol: & Exptl:. Therap:. 85", 78 (1945:).] has. shown that this, connection; the rain; as» its- free.base; is' an approx.. 2;4>. times so-, strongly acting local anaesthetic. as procaini This hydrochloride'has a. acute intra-travenous toxicity'. (LD^0).'in mice at 24 0;5v mg/kg.

Other:'methiodide salts. was prepared as follows: 9-[N-(2;6-dimethylphenyl.)carbamylethyl]-granatanine. [!;' R and; R' is CH 3 ; R" is H; YT is, CH'2CH'2; n: is 2.; A. is CH2] prepared from N-(-2,6rdimethylphenyl)carbamylethyl chloride' . granatanine: and. hot free sodium carbonate. i: ethanol was: treated, in solution: in acetone, with methyl iodide~ and: one obtained 9>NV (2,6-dimethylphenyl)carbamylethyl^granatanine methiodide, m.p. 224.4—228.0° C. (corr.;)in Analysis: Calculated, for C20HJ31 JN2ff.: C = 54.25;

H = 7.06; J = 28.66^

Found: C = 54.07;: H: = 6.98; J > = 28.44.

9- [N-(2;6-dimethylphenyl)carbamylethyl]-3-p-hydroxy-granatanine: [I;. R and.. R' are

CH3; R" is IT; Y' is CH^GH2; n-er2-; A is CHOH>], prepared from N-(2,6-dimethylphenyl>carbamylethyl chloride, 3[3-hydroxygranata-nine, and' anhydrous sodium carbonate i' ethanol'; was treated in acetone solution^ with methyl iodide and 9-[N-(2,6-dimethylethylphenyl)carbamylethyl]-3-|3-hydroxygranatanine methiodide was obtained m.p. 217;4-22r, 4° C (corr.).

Analysis:

Calculated for C20H31JN2O2: G = 52.40;

H = 6.82; J =-- 2.7,70.

Found: C = 52.81; H = 6.74. J = 27.69.

9- [N-(2,6-dimethylphenyl)carbamylmethyl]-3-(3-hydroxygranatanine [ I; R and R' are GHv,; R" is. H; Y is GH2; n is 2; A is CHOH ], prepared from N-(2,6-dimethylphenyl)carbamylmethyl chloride, 3-p-hydroxygranatanin and anhydrous sodium carbonate in ethanol, was treated in acetone solution with methyl iodide to give 9-[N-(2, 6-dimethylphenyl)carbamylmethyl]-3-(3-hydroxy-granatanine-methbdid. m.p. 228.4-229.4° C. (corr.).

Analysis:

Calculated, for C1()H2[)JN2O2: G = 51.45;

H = 6.58; J = '28.55-"

Found: G = 51.41; H, = 6.65; J = 28.12.

9>[N-(2,6-dimethylphenyl)carbamylmethyl].-A2-granatenine [A is CH = R, and. R' is CH 3 ; R" is H> Y is CH2; n is. 2], prepared from N-(2,6-dimethylphenyl)carbamylmethyl chloride; A2-granatenine and anhydrous sodium carbonate in ethanol, was treated in acetone solution with methyl iodide and man gave 9-[N-(2;6-dimethylphenyl)carbamylmethyl]r A2-granatenine methiodide=, mp 214-.6— 217.4° C (corr.).

Analysis:

Calculated, f br. C19H27J<N>20: C. = 53.50;,

H = 6.38; J = 29.75.

Found: C, = 53.22;. H 6.42; J = 29.45.

9-[N-(2,6-dimethylphenyl)carbamylethyl]-A2-granatenine [A is CH= R and. R' is CH 3 ;

R" is H;. Y. is CH2CH'2; n is 2], prepared from N-(2,6-dimethylphenyl)carbamylmethyl chloride, A2-granatenine and anhydrous sodium carbonate in ethanol, was treated in acetone solution .with methyl iodide and man; obtained 9- [N.-(2;6-dimethylphenyl.)carbamylethyl]-A2-granatenine-methbdide, m.p.: 215.6— 218*0 °C (corr:). ;Analysis : ;Calculated for C20H29J<N>2O: ,C = 54.50; ;H= 6.63; J = 28.80 ;Found: C = 54.70; H = 6.67; J =.28.47 If, in the preparation described above, N-(2,6-dimethylphenyl)carbamylmethyl chloride is replaced by a molar equivalent amount of N-phenylcarbamylmethyl chloride, N-(2-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-rbutoxyphenyl») carbamylmethyl chloride; (prepared from 2,6-dimethyl-4-n-butoxyaniline and chloroacetyl chloride), one obtains, respectively, 8-(N-phenylcarbamylmethyl) ^3-hydroxynortropane [I; R, R' and .R" is H, Y is CH0, n is 1, A is CH(OH); ,8-[N-(,2-methyl-6~-chlorof enyl)carbamylmethyl]-3-hydroxy-nortropane [I; R-is CH.,, R'is Cl, R" is H, Y is CH2, n is 1, A" is CH(OH); 8-[N-(2j4,6-trimethylphenyl)carbamylmethyl]-3 hydroxynortropane [I; -R, -R' and R" are CH.,, Y is CH2, n is 1, A is CH(OH); :8-,[N-(24,6-triisopropylphenyl)carbamylmethyl]- 3-hydroxy-nortropane [I; R, R' and R" are CH(CH3)2, Y is CH2, n is 1, A is CH(OH); or 8-[N-(2,6-dimethyl- 4-n-butoxyphenyl)-carbamylmethyl]-3-hydroxynortropane [I; R and R' are CH3, R" is C(.CH9)3CH.,, Y is CH2, n is .1, A is CH(.OH )]. ;If in the above preparation one replaces N-(2,6-dimethylphenyl)carbamylmethyl chloride with a molar equivalent amount of 1-methyl-2-[N-(2,6-dimethylphenyl)carbamyl] ethyl chloride (prepared from 2,6-dimethylaniline and |5-chlorovaleryl chloride) or 5- [N-(2,6-dimethylphenyl)carbamyl]-pentyl chloride (prepared from 2,6-dimethylaniline and ε-chlorocaproyl chloride ), gives respective 8-[1-methyl-2-[N-(2,6-dimethylphenyl)carbamyl]ethyl]-3-hydroxynortropane; [I; R and R' are CH,,, R" is H, Y is CH2CH(CH3), n is 1, A is CH(OH)]; or 8-[5-N-(2,6-dime tylphenyl)carbamyl]pentyl]-3-hydroxynortropane [I; R and R' are CH3, R" is H, Y is (CH2)5, n - is 1, A is 'CH(OH)]. ;In the above preparation, replacing nortropine with a molar equivalent amount of 3-garnetaniol gives man 9- [N-(2,6-dimethylphenyl)carbamylmethyl]-;3-hydroxy-granatenine [I; R and R' are CH3, R" is,H, Y is CH2, n is 2, A is CH(OH)]. ;,If in the above process one replaces nortropine with 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), 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-oxonortropane [I; R<q>g R' is CH3, R" is H, Y is CH.„ n -is 1, A -is C = O]; 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3 -chloro-nortropane [I; R and R' are CH3, R" is H, Y is CH2, n is 1, A is CHClf; ;18- [N-(2,6-dimethylphenyl)carbamylmethyl]-3-bromonortropane [:I; R and R' are CH. , R and R' are CH3, R" is H, Y is CH2, n is 1, A is CH(OCOC6H5)]; ; or 8-[N-(2,6-Dimethylphenyl)carbamylmethyl]-3H-hydroxy-3-methylnortropane [I; Rog R' is CH,„ R" is H, Y is CH,, n is 1,,A is C(OH)(CH3.)]. ;8-[N-(2,6-dimethylphenyl) carbamylmethyl] -3-hydroxy-nortropane -can react with hydrochloric acid, hydrobromic acid, .hydroiodic acid, sulfuric acid, acetic acid, -quinic acid, 2-naphthalenesulfonic acid, phosphoric acid, methyl iodide, methyl bromide, ethyl bromide, allyl bromide, benzyl chloride, o-chlorobenzyl chloride, methyl-p^ toluene sulfonate or methyl sulfate and then gives the respective hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, acetate, quinate, 2-naphthalene sulfonate, phosphate or acid phosphate, methiodide, metbromide, etbromide, allobromide, benzochloride, o-chlorobenzochloride, met- the o-.toluenesulfonate or metsulfate as salt. ;Example 2. ;8-.[N- 2, 6-;dimethylphenyl)cafbamyl-methyl] nortropane ;[I; R and R' are CH3, -R" is :H, Y is \CH2, n's .1, A is CH2]. ;A mixture of 5.9 g (0.030 mol) N-(2,6-dimethylphenyl) carbamylmethyl chloride and 7.0 g (0.063 mol) nortropane in 150 ml dry benzene was heated under reflux for 8 hours . After the reaction mixture was allowed to stand overnight, the white precipitate of nortropane hydrochloride was separated by filtration and washed with benzene. The combined filtrate plus washing liquid was washed with . 2 portions of water, each of 50 ml, and then extracted with dilute hydrochloric acid (4 ml of concentrated hydrochloric acid in 50 ml of water), and washed with water to a neutral reaction. The acid extracts were combined, filtered and basified with ammonium hydroxide. The product was filtered off, dissolved in 700 ml of hot hexane, and the solution was filtered and concentrated to a volume of .300 ml. 7.2 g of 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-nortropane was then prepared, which was recrystallized from 350 ml of hexane and dried over phosphorus pentoxide at 80° C. and 0.2 mm for 6 hours, whereby obtained a product with m.p. 154—155° C (corr.). ;Analysis: ;Calculated for CJ7H94N90: 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)-carbamylmethyl]nortropane 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 . The solution was filtered while hot and then cooled to 5°C, whereupon the product separated. The salt was recovered by filtration, washed with cold isopropyl alcohol and dry ether, dried at 70° C. for 20 hours, and water then gave 40.5 g of product which melted at 233-236° C. (corr.). ;Analysis: ;Calculated for C]7H.,4N,0 . HC1:C1 = 11.47; ;N = 9.07 ;Found: Cl = 11.44; N = 8.95: ;A pharmacological evaluation of 8-[N-(2,6-dimethylphenyl)carbamylmethyl]nortropane hydrochloride in aqueous solution applied intracutaneously to guinea pigs by the method specified by Bulbring and Wajda, 10c, eit., shows that this compound, calculated as its free base, is approx. 7.5 times as active as a local anesthetic as procaine, and 2.3 times as active as lidocaine, 8-[N-(2,6-dimethylphenyl) carbamylmethyl] nortropane hydrochloride was shown to have an acute vitreous toxicity (LDr, 0) in mice of 10.5 ± 0.9 mg/kg. By allowing N-(2,6-dimethylphenyl)carbamylmethyl chloride to react with 3-(3-hydroxygranatenine by the method described above in example 2) 9-[N-(2,6-dimethylphenyl)carbamylethyl]-3 was obtained -(3-Hydroxygranatenine [I; R and R' are CH3; R" is H; Y is CH0CH.,; n is 2; A is CHOH], mp 161.2—163<*>4<0> C (corr.).

Analysis:

Calculated for C^H^N^O;,: C = 72.05;

H = 8.92; N ="8.25"

Found: C = 71.92; H = 9.20; N = 8.69.

Example 3.

8-[N-2,6-dimethylphenyl)carbamylmethyl]nortropidine

[A is CH = R and R' is CH:i, R" is H, Y

is CH2, n is 1] was prepared from 5.9 g (0.030 mol) N-(2,6-dimethylphenyl) carbamylmethyl chloride and 6.9 g (0.063 mol) nortropidine in 150 ml of dry benzene by the in Example 2 described method. 4.6 g of 8-[N-(2,6-dimethylphenyl)carbamylmethyl]nortropidine were obtained, m.p. 161.5—164° C (corr.). After recrystallization from a mixture of benzol and hexane.

Analysis:

Calculated for C17H22N;)0: N(total) = 10.36;

N(basic) = 5.18."

Found: N(total) = 10.31; N(basic) = 5.13'

A pharmacological evaluation of 8-[N-(2,6-dimethylphenyl) carbamylmethyl] nortropidine in the form of an aqueous solution of its acid addition salt, used intracutantly on guinea pigs, according to Bulbring and Wajda's method 10c, eit., has shown that this compound, considered as a free base, is approx. 2.7 times as active as a local anesthetic such as procaine. 8-[N-(2,6-dimethylphenyl)carbamylmethyl]nortropine was found to have an acute intravenous toxicity (LDf)0) in mice of 13 ± 1.2 mg/kg.

Example 4.

8-[ N- 2, 6- dimethylphenyl) carbamylmethyl^ pseudo- 3- hydroxy- nortropane

[IN; R and R' are CH.,, R'' is H, Y is CH9, n is 1, A is CH(OH)]."

A mixture of 5.9 g (0.030 mol) of N-(2,6-dimethylphenyl)carbamylmethyl chloride,

8.0 g (0.063 mol) of pseudonortropine in 100 ml of absolute ethanol was heated at reflux for 8 hours. The reaction mixture was allowed to stand overnight and was then concentrated in vacuo. The residue was heated with 100 ml of chloroform for several hours under reflux and the insoluble pseudonortropin hydrochloride was separated by filtration and washed with chloroform. The combined chloroform filtrate plus the washings were washed with 3 portions of water, each of 25 ml, extracted with dilute hydrochloric acid (5 ml of conc. hydrochloric acid in 50 ml of water), and finally washed with 4 portions of water, each of 10 ml. The combined acid extracts and washing solutions were filtered, and made alkaline with conc. ammonium hydroxide. The product that stood out was

collected and dissolved in 200 ml of benzol, and

the solution was filtered, concentrated to

75 ml., and diluted with 30 ml of hexane. Mon

then got 7.1 g of 8-[N-(2,6-dimethylphenyl)carbamylmethyl] pseudo-3-hydroxynortropane,

which was further purified by successive recrystallizations from benzenehexane, ethylacetatehexane and ethyl acetate, and then dried at room temperature over phosphorus pentoxide at 0.1 mm pressure for 24 hours, whereby a product was obtained which had m.p. 176.5— 178.5° C (corr.). A melting point determination of a mixture with the 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-hydroxynortropane obtained in example la showed a lowering to 149-160°C.

Analysis: Calculated for Cl7H.4N.09: N(total) = 9.72;

N(basic) = 4~.86." Found: N(total) = 9.52; N(basic) = 4.82.

Pharmacological assessment of 8-[N-(2,6-dimethylphenyl) carbamylmethyl] pseudo-3-hydroxynortropane in an aqueous solution of its acid addition salt applied intracutaneously to guinea pigs by the method specified by Bulbring and Wajda, 10c, eit., shows that this connection, considered as a free base, enj approx. 0.9 times as active as a local anesthetic as procaine. 8-[N-(2,6-dimethylphenyl)carbamylmethyl]pseudo-3-hydroxy-nortropane was found to have an acute intravenous toxicity (LD50) in mice of 58 4.8 mg/kg .

Example 5.

8-[ N- 2, 6- dimethylphenyl) carbamyl-ethylJ- 3- hydroxynortropane

[IN; R and R' are CHS, R" is H, Y is CH.,CH.„ n is 1, A is CH(OH)]

A mixture of 12.7 g (0.060 mol) N-(2,6-dimethylphenyl)carbamylethyl chloride, 8.0 g (0.063 mol) nortropine and 6.4 g (0.06 mol) anhydrous sodium carbonate in 200 ml absolute ethanol was heated at reflux for 20 h. The inorganic solids were removed by filtration, washed with ethanol, and the combined washings plus the ethanol filtrate were concentrated in vacuo. The residue was dissolved in 200 ml of dilute acetic acid, the solution was filtered through filter-cell, and then basified with solid potassium carbonate. The mother liquors were decanted from the resulting gummy substance, which was then washed with water and dissolved in chloroform. The chloroform solution was washed with 50 ml of water, filtered and concentrated. vacuum. The resulting pale yellow oil was dissolved in 150 ml of boiling benzol, the solution was filtered and concentrated to 75 ml, and then 35 ml of hexane was added, whereby 10.6 g of a crystalline pro-

duct, which melted at 117—119° C. This

product was recrystallized 2 times from a benzene-hexane mixture and then 2

times from ethyl acetate and then dried for 5 hours over phosphorus pentoxide at 100° C. and 0.05 mm pressure, whereby 8-[N-(2,6-dimethylphenyl) carbamylethyl]-3-hydroxynortropane, m.p. 151—153° C (corr.).

Analysis:

Calculated for C18H2(;N.-,0=,: N(total) = 9.27;

N(basic) = 4.63?

Found: N(total) = 9.06; N(basic) = 4.62.

Pharmaceutical evaluation of 8-[N-(2,6-dimethylphenyl) carbamylethyl]-3-hydroxy-nortropane in an aqueous solution of its acid addition salt, applied intracutaneously to guinea pigs by the method indicated by Bulbring and Wajda, 10c, eit., have shown that this compound, considered as a free base, is approx. 1.2 times as active as a local anesthetic such as procaine. It was found that 8-[N-(2,6-dimethylphenyl)-carbamylmethyl]-3-hydroxy-nortropane had an acute intravenous toxicity (LD50) in mice of 6.8 ± 0.4 mg/kg. Using the procedure just described and appropriate other reactants, other N'-[N-(monocarbocyclic aryl)carbamyl-lower alkyl]-1,5-iminocycloalkanes and -iminocycloalkanes were prepared as follows: 9-[N-(2 ,6-dimethylphenyl)carbamylmethyl]-3-a-hydroxygranatenine [I; R and R' are CHS;

R" is H; Y is CH.,; n is 2; A is CHOH],

m.p. 169.6—172.0° C (corr.).

Analysis:

Calculated for ClsH.,(1NnO./. C = 71.49;

H = 8.67; N = 9^27"

Found: C = 71.24; H = 8.70; N = 9.15.

9- [N-(2,6-Dimethylphenyl)carbamylethyl]-3 -

α-Hydroxygranatenine [I; R and R' are CH,,;

R" is H; Y is CH 2 CH.,; n is 2; A is CHOH], m.p. 168.8-171.2° C" (corr.).

Analysis:

Calculated for C|(|H.,8N.,0,: C = 72.12; H =

8.92; N = 8.86"'

Found: C = 72.11; H = 9.06; N = 8.78.

9-[N-(2,6-dimethylphenyl)carbamylmethyl]-granatenine [I; R and R' are CH,,; R" is H;

Y is CH.,; n is 2; A is CH.,] m.p. 167.2—

170.2° C "(corr.).

Analysis:

Calculated for C1sHOfiN,,0; C = 75.48; H =

9.15; N = 9.78"

Found: C = 75.28; H = 9.09; N = 9.72.

9- [N-(2,6-dimethylphenyl)carbamylmethyl]-3-p-hydroxygranatenine [i; R and R' are CH. R" is H; Y is CH.,; n is 2; A is CHOH], mp. 155.8-157.4° "c (corr.).

Analysis:

Calculated for CIHH.MiN,0.,: C = 71.55; H =

8.67; N = 9.28"

Found: C = 71.54; H = 8.88; N = 9.13. 1-[8-[N-(2,6-dimethylphenyl)carbamyl-1-ethyl]]-3-[3-hydroxynortropane [I; R and R' are CH 3 ; R" is H; Y is CH(CH^), n is 1; A is CHOH], m.p. 185.6—188.6°°C (corr.). Analysis: Calculated for Cl8H2(iN90,: C = 71.49; H = 8.67; N = 9.27. Found C = 71.73; H = 8.82; N = 9.16 l-[8-[N-(2,62-dimethylphenyl) carbamyl-1 - ethyl]]-nortropane [I; R and R' are CH,,; R" is H; Y is CH(CH,); n is 1; A is CH.",], m.p. 127, 8—129.4° C (corr.). Analysis: Calculated for Cl8H.)(iN.,0: C = 75.48; H 9.15; N = 9.78"

Found: C = 75.69; H = 9.03; N = 9.64.

8- [N-(2,4,6-trimethylphenyl)carbamylmethyl]-3-α-hydroxynortropane [I; R, R' and R" are CH 1 , Y is CH 2 ; n is 1; A is CHOH], mp 177.8-179.0° C (corr.).

Analysis:

Calculated for C, sH9(1N0O9: C = 71.49; H =

8.67; N = 9,277

Found: C = 71.20; H = 8.37; N = 8.97

8- [N-(2,4,6-trimethylphenyl)carbamylmethyl]-nortropane [I; R, R' and R" are CH,,; Y is CH,; n is 1; A is CH,], mp 180.2-181.8° C (corr.).

Analysis:

Calculated for C,sH 9 0 N,O: C = 75.48; H =

9.15; N = 9.78."

Found: C = 75.58; H = 8.94; N = 9.72.

9- [N-(2,4,6-trimethylphenyl)carbamylmethyl]-3-a-hydroxygranatenine [I; R, R' and R" are CH 3 ; Y is CH 2 ; n is 2; A is CHOH], mp 145.2-145.8° C (corr.).

Analysis:

Calculated for C^H^NoO.,: C = 72.17; H =

8.92; N = 8.86."

Found: C = 72.26; H = 8.37; N == 8.96.

9- [N-(2,4,6-trimethylphenyl)carbamylmethyl]-granatenine [I; R, R' and R" are CH,,; Y is CH,; n is 2; A is CH2], mp 199.7-201.8° C (corr.).

Analysis:

Calculated for C^H^ISU): C = 75.96; H =

9.39; N = 9.33."'

Found: C = 76.22; H = 9.03; N = 9.36. 1-[9-[N-(2,6-dimethylphenyl)carbamyl-1-ethyl]]-3-a-hydroxy-granatenine [I; R and R' are CH 3 ; R" is H; Y is CH(CH3); n is 2;

A is CHOH], m.p. 187.2—189.9°'c (corr.). Analysis: Calculated for C|(|H.,8N,02: C = 72.10; H 8.92; N = 8.857

Found: C = 72.42; H = 8.71; N = 8.83. 1-[8-[N-(2,6-dimethylphenyl)carbamyl-1-ethyl]]-3-p-hydroxynortropane [I; R and R' are CH,,; R" is H; Y is CH(CH3); n is 1; A is CHOH], m.p. 200.4—203.2° C (corr.). Analysis: Calculated for Cl8H2(1N20,: C = 71, 45;H =

8.66; N = 9.25.

Found: C = 71.59; H = 8.63; N = 9.31. 1-[9-[N-(2,6-dimethylphenyl)carbamyl-1-ethyl]]-3-p-hydroxygranatenine [I; R and R' are CH,,; R" is H; Y is CH(CH,,); n is 2; A is CHOH], mp. 179.2—183.0° C (corr.). Analysis: Calculated for C1,)H.,8N90 „; C = 72.10; H =

8.92; N = 8.85".

Found: C = 72.31; H = 8.78; N = 8.87.

8- [N-(2,4,6-trimethylphenyl)carbamylmethyl]-3-(3-hydroxynortropane [I; R, R' and R" are CH3; Y is CH,; n is 1; A is CHOH] , mp 123.4—125.6° C (corr.).

Analysis:

Calculated for C18H9(iN,02: C = 71.49; H =

8.67; N = 9.27".

Found C = 71.76; H = 8.55; N = 9.27.

9- [N-(2,4,6-trimethylphenyl)carbamylmethyl]-

3-p-hydroxygranatenine [I; R, R' and R" are CH 3 ; Y is CH 1 ; n is 2; A is CHOH], mp 185.0-186.0° C (corr.).

Analysis:

Calculated for CiqH28N2O2: C == 72.04; H =

8.92; N = 8.85.

Found: C = 72.23; H = 9.07; N = 8.75. 1-[8-[N-(2,4,6-trimethylphenyl)carbamyl-1-ethyl]]-nortropane [I; R, R' and R" are CH,; Y is CH(CH,,); n is 1; A is CH9], mp 134°.8—137.4° C (corr.).

Analysis:

Calculated for C|()H98 N.,0: C = 76.00; H =

9.40; N = 9.32".

Found: C = 75.66; H = 9.15; N = 9.30.

8- [N-(2,6-dimethylphenyl)carbamylethyl]-3-p-hydroxynortropane [I; R and R' are CH 3 ;

R" is H; Y is CH,CH2; n is 1; A is CHOH], mp 139.8-141.4° C (corr.).

Analysis:

Calculated for Cl8H9(iN,02: C = 71.50; H =

8.67; N = 9.27".

Found C = 71.20; H = 8.77; N = 9.56.

9-[N-(2,6-dimethylphenyl)carbamylethyl]-granatenine [I; R and R' are CH,,; R" is H; Y is CH,CH9; n is 2; A is CH9], mp 109.0-113.8° C (corr.).

Analysis:

Calculated for C1;|H9SN:)0: C = 75.96; H

9.39; N = 9.33."'

Found: C = 76.16; H = 9.33; N = 9.06.

9-[N-2,6-dimethylphenyl)carbamylethyl]-A2-granatenine [A is CH = R and R' is CH3; R" is H; Y is CH„CH.,; n is 2], m.p. 125.4-129.2° C (corr/).

Analysis:

Calculated for C,(|H.,(iN90: C = 76.50; H =

8.79; N = 9.40"!

Found C = 76.63; H = 8.99; N = 9.23.

9- [N-(2,6-dimethylphenyl)carbamylmethyl]-A--granatenine [A is CH = R and R' is CH,,; R" is H; Y is CH9; n is 2], mp 152.0-154.0° C (corr.).

Analysis:

Calculated for C,sH.MN90: C = 76.01; H =

8.51; N = 9.85."

Found: C = 76.11; H = 8.44; N = 9.91. 1 -[8- [N-(2,6-dimethylphenyl)carbamyl-1-ethyl]]-A2-nortropene [A is -CH = R and R' is CH,,; R" is H; Y is CH(CHH); n is 1], m.p. 138.6-140.2° C. (corr.).

Analysis:

Calculated for CISH.,4N.,0: C = 76.01; H =

8.51; N = 9.85T

Found: C = 76.12; H = 8.73; N = 9.79. 1-[9-[N-(2,6-dimethylphenyl)carbamyl-1-ethyl]]-A2-granatenine [A is -CH = R and R' is CH,,; R" is H; Y is CH(CH,,); n is 2], mp 98.0-109.4° C (corr.).

Analysis:

Calculated for C|()H9(iN90: C = 76.50; H

8.78; N = 9^38."

Found: C = 76.47; H = 9.06; N = 9.14.

9- [N-(2,4,6-trimethylphenyl)carbamylmethyl]-A2-granatenine [A is -CH = R, R' and R" are CH.{; Y is CH.,; n is 2], mp 171.8^-174.0° C (corr.).

Analysis:

Calculated for C|(|H9(iN90: C = 76.47; H =

8.78; N = 9,397

Found C == 76.59; H = 8.91; N = 9.33.

9-[N-(2,4,6-trimethylphenyl)carbamylmethyl]-A2-nortropene [A is -CH = R, R' and R" are CHH; Y is CH0; n is 1], mp 122, 2—123.4° C (corr.).

Analysis:

Calculated for Cl8H94N:iO: C = 76.01; H =

8.51; N = 9,857

Found: C = 76.00; H = 8.30; N = 9.88.

8-[N-(2,6-dimethylphenyl)carbamylethyl-A2-nortropene [A is -CH = R and R' is CH3;

R" is H; Y is CH,CH9; n is 1], mp 144.6— 147.0° C (corr.)." '":

Analysis:

Calculated for CISH94N:,0: C = 76.00; H

8.51; N 9.85".

Found: C = 76.06; H = 8.66; N = 9.93.

Example 6.

8-[N-2,6-dimethylphenyl)carbamylethyl~\nortropane

[IN; R and R' are CH,,, R" is H; Y is CH9CH2, n is 1, A is CH,] was prepared from 8.5 g (0.040 mol) of N-(2,6-dimethylphenyl)carbamylethyl chloride , 4.7 g (0.042 mol) nortropane and 4.2 g (0.04 mol sodium carbonate in 200 ml absolute ethanol, by the method described in example 5. 9:9 g 8-[N-(2,6 -dimethylphenyl)carbamylethyl]-nortropane, mp 119-122° C (corr.) after recrystallization from hexane.

Analysis:

Calculated for C1sH2(iN90: N(total) = 9.78;

N(basic) = 4.89."

Found: N(total) = 9.73; N(basic) = 4.85.

A pharmacological evaluation of 8-[N-(2,6-dimethylphenyl) carbamylethyl]-nortropane in the form of an aqueous solution of its acid addition salt, applied intracutaneously to guinea pigs, according to the method stated by Bulbring and Wajda, 10c. eit., shows that this compound is about 4 times as active as a local anesthetic as procaine. The substance was found to have an acute intravenous toxicity (LDno) in mice of 8.6 0.6 mg/kg.

Example 7.

8-[ N- 2, 6- dimethylphenyl)carbamylmethyl]- 3- acetoxynortropane

[IN; R and R' are CH3, R" is 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 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 for 2 hours on a steam bath, and then concentrated in vacuo. The residue was dissolved in 25 ml of absolute ethanol, and the solution was concentrated in vacuo. The residue was dissolved in 200 ml of dilute acetic acid, the solution was filtered through a filter cell and then made basic with potassium carbonate. The mixture was cooled and the product was collected by filtration and recrystallized from hexane, whereby 4.1 g of product was obtained, which melted at 129-131° C. This product was recrystallized from a mixture of 25 ml of benzol and 50 ml of hexane, and dried for 8 hours over phosphorus pentoxide at 100° C. and 0.3 mm pressure, whereby 3.9 g of 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-acetoxy-nortropane was obtained, m.p. 142.5—144.5° C (corr.).

Analysis:

Calculated for CiqH9(.N0O3: C = 69.06; H =

7.93; N = 8,487

Found: C = 68.90; H = 8.07; N = 8.32.

Pharmacological assessment of 8-[N-(2,6-dimethylphenylcarbamylmethyl]-3-acetoxy-nortropane in an aqueous solution of its acid addition salt applied intracutaneously to guinea pigs according to the method indicated by Bulbring and Wajda, 10c. eit., shows that this compound considered as a free base has approximately the same local anesthetic effect as procaine.The substance was found to have an acute intravenous toxicity (LD50) in mice of 30 ± 1.6 mg/kg.

If, in the method described above, the acetic anhydride is replaced by a molar equivalent amount of cinnamoyl chloryl, 3,4,5-trimethoxybenzoyl chloride, N,N-dimethylcarbamyl chloride, hexanoyl chloride, succinic anhydride or phenylacetyl chloride, the respective 8-[ N-(2,6-dimethylphenyl)carbamylmethyl]-3-cinnamoyloxynortropane [I; R and R' are CH3, R" is H, Y is CH2, n is 1, A is CHOCOCH = CHC6H5]; 8-[N-(2,6-dimethylphenyl)-carbamylmethyl]-3-trimethoxybenzoyl nortropane [I; R and R' is CH3, R" is H, Y is CH.„ n is 1, A is CHOCOC(jH2(OCH3)3]; 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-dimethyl -carbamyloxynortropane [I; R and R' are CH3, R" is H, Y is CH2, n is 1, A is CHOCON (CH3)2].; 8-[N-(2,6-dimethylphenyl)carbamylmethyl]- 3-Hexanoyloxynortropane [I; R and R' are CH3, R" is H, Y is CH9, n is 1, A is CHOc6(CH2)4CH3]; 8-[N-~(2,6-dimethylphenyl)carbamylmethyl ] -3-([3-carboxy-propionyloxy)-nortropane [I; R and R' are CH3, R" is H, Y is CH.„ n is 1, A is CHOCOCH2CH2COOH]; or 8-[N-( 2,6-dimethylphenyl)carbamylmethyl]-3-phenylace-toxinortropane [I; R and R' are CH 3 , R" is H, Y is CH 2 , n is 1, A is CHOCOCH 2 CGHr)].

Example 8.

8- [ N- 2, 6- dimethylphenyl) carbamylmethyl] - 3- propionyloxy nortropane

[IN; R and R' are CH3, R" is H, Y is CH.„ n is 1, A is CHOCOC2H5] was prepared from 5 g of 8-[N-(2,6-dimethylphenylcarbamylmethyl]-3-hydroxynortropane and 5 g of propionic acid an -hydride in 25 ml of pyridine by the method described in Example 7. This compound melted at 143-144° C (corr.) after recrystallization from a benzene-hexane mixture.

Analysis:

Calculated for C.J0H28N2O,;: C = 69.47; H =

8.19; N = 8.14.

Found: C = 69.84; H = 8.02; N = 7.91.

Example 9.

8-[ N- 2, 6- dim ethylphenyl) carbamylethyl'] - 3- acetoxynortropane

[IN; R and R' are CH,., R" is H, Y is CH2CH2, n is 1, A is CHOCOCH3] was prepared from" 4 g of 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-hydroxynortropane and 4 ml of acetic anhydride in 20 ml of pyridine by the method described in example 7. This compound melted at 119-123°C (corr.) after recrystallization from a mixture of benzol and hexane.

Analysis:

Calculated for C90H,sN:)O3: C = 69.74; H =

8.19; N = 8.14.'

Found: C = 69.43; H = 8.46; N = 7.91.

A pharmacological evaluation of 8-[N-2,6-dimethyl (phenyl)carbamylethyl]-3-acetoxynortropin in an aqueous solution of its acid addition salt, applied intracutaneously to guinea pigs according to the method of Bulbring and Wajla, 10c. eit., shows that this compound, considered as a free base, is approx. 1.3 times as active as procaine as a local anesthetic.

Example 10.

8-\_ N- 2, 6- dimethylphenyl) carbamylmethyl]- 3- propionyloxynortropane [I; R and R' are CH3, R" is H, Y is CH0, n is 1, A is CHOCOC2H5] was prepared from 5 g of 8-[N-(2,6-dimethylphenyl)-carbamylmethyl]-3-hydroxynortropane and 5 g of propionic anhydride in 20 ml of pyridine by the method described in example 7. 5.5 g of 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-propionyloxynortropane, m.p. 109-111° C (cor. .) after recrystallization from hexane.

Analysis:

Calculated for C21H30<N>2<O>3<:> C = 70.35; H =

8.44; N = 7.82; O = 13.39.

Found: C = 70.58; H = 8.39; N = 7.63;

O = 13.45.

Example 11.

(a) Nor-α-ecgonine methyl ester.

Nortropine hydrochloride (48.5 g, 0.30 mol) was added portionwise over 15 minutes to a solution of 21.5 g (0.33 mol) of potassium cyanide in 75 ml of water. The solid cyanohydrin that separated was filtered off, washed with pyridine and dried over phosphorus pentoxide. The cyanohydrin (56 g) was added portionwise with stirring to 500 ml of concentrated hydrochloric acid at 10-15° C. The mixture was stirred for several hours, allowed to stand overnight at room temperature, and then concentrated in vacuo. The residue was dried by adding benzol and distilling off the benzene in vacuum. The residue was washed with acetone, the solid product was collected and heated under reflux in 400 ml of ethanol on a steam bath for 4 hours while hydrogen chloride gas was bubbled through. The solution was allowed to stand at room temperature for 66 hours and was then concentrated in vacuo. The rest was dissolved in approx. 100 ml of water, decolorized with activated charcoal, and the solution was then treated with solid potassium carbonate until a solid, white substance separated. The mixture was extracted with three portions of chloroform, each of 100 ml, and the chloroform solutions were dried over anhydrous calcium sulfate and concentrated to give 22.8 g of solid product. The aqueous layer was further saturated with potassium carbonate and the solid which separated was collected and washed with three portions of chloroform, each of 100 ml. The chloroform washing solutions were used to extract the aqueous filtrate, and after drying and concentration gave an additional 5.5 g of solid product. The combined solid products were recrystallized from 200 ml of ethyl acetate and gave 15.6 g of nor-α-ecgonine methyl ester, m.p. 143-145° C.

(b) 8- [ N - ( 2, 6- dimethylphenyl) carbamylmethyl]- 3- hydroxy- 3- carbo-methoxynortropane

[IN; R and R' are CH3, R" is H, Y is CH.„ n is 1, A is C(OH) (COOCH,,)].

A mixture of 5.7 g (0.030 mol) N-(2,6-dimethylphenyl)carbamylmethyl chloride,

5.6 g (0.030 mol) nor-α-ecgonine methyl ester

and 3.5 g (0.033 mol) of anhydrous sodium carbonate in 250 ml of ethanol was heated at reflux for 5 hours. The reaction mixture was prepared in the manner described in example 5. 5.9 g of 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-3-hydroxy-3-carbomethoxynortropane were obtained, m.p. 197-199° C (corr.) after recrystallization from ethyl acetate.

Analysis:

Calculated for O^H^N^: C = 65.87; H =

7.57; N = 8.09.

Found: C = 65.55; H = 7.24; N = 8.07.

Example 12.

(a) Nortropin-one- ethylene glycol- ketal.

A mixture of 48.5 g (0.30 mol) of nortropine hydrochloride, 90 ml (1.5 mol) of ethylene glycol and 1 g of p-toluenesulfonic acid monohydrate in 500 ml of dry benzene was heated for 19 hours under reflux, under a water separator. The excess of benzol and ethylene glycol was then removed in a vacuum in a steam bath. The remainder was stirred with approx. 400 ml of dry acetone and filtered, whereby 41.9 g of solid product was obtained. The filtrate was concentrated in vacuo to remove the acetone and the rest of the ethylene glycol, and the residue was again treated with acetone, whereby a further 11.9 g of solid product was obtained. The two portions of solid product were combined and stirred with 75 ml of saturated potassium carbonate solution. Chloroform was added, the mixture was stirred and the chloroform solution was separated. The aqueous mixture was filtered to remove inorganic salts, which was washed with chloroform. The aqueous filtrate was extracted with chloroform, and the combined chloroform extracts and washings were filtered through anhydrous calcium sulfate and concentrated in vacuo. The residue was distilled through a Vigreux column and the fraction boiling at 68-69°C (0.7-0.8 mm) was collected and redistilled to give 34.2 g of nortropinone-ethylene glycol ketal, bp . 70°C (0.8mm).

(b) 8-IN-(2,6-dimethylphenyl)carbamylmethyl]nortropinone-ethyleneglycol-ketal was prepared from 7.9 g (0.040 mol) N-(2,6-dimethylphenyl)carbamylmethyl chloride, 7.4 g (0.044 mol) of nortropinone-ethylene-glycol-ketal and 6.4 g of anhydrous sodium carbonate in 200 ml of absolute ethanol, by the method described in Example 1. The product was isolated in the form of the free base and recrystallized successively from benzol hexane, ethyl

acetate-hexane and the ethyl acetate, whereby: 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-nortropinone ethylene glycol ketal was obtained, with m.p. 126-129°C.

Analysis: Calculated for C1()Ho(.Nt,0<.: C = 69.06; H = 7.94; N = 8.48? Found: C = 69.33; H = 8.08; N = 8.46. (c) 8-[N-(2,6-dimethylphenyl)carbamylmethyl]nortropinone [I; R and R' are CH3, R" is H, Y is CH2, n is 1, A is C = O].

A mixture of 2.4 g of 8-[N-(2,6-dimethylphenyl)-carbamylmethyl]-nortropinone-ethylene-glycol-ketal, 2 ml of concentrated hydrochloric acid and 15 ml of water was kept at room temperature for approx. 70 hours. The reaction mixture was basified with saturated potassium carbonate solution, and the solid that separated was filtered off and dissolved in chloroform. The chloroform solution was filtered through anhydrous calcium sulfate and concentrated in vacuo. The residue was dissolved in 50 ml of boiling benzol and the solution was filtered, concentrated to 25 ml and diluted with 75 ml of hexane. The solution was cooled and the product which separated out was filtered off, recrystallized from 25 ml of benzene and 75 ml of hexane and dried over phosphorus pentoxide at 100° C. and 0.2 mm for 6 hours, thereby obtaining 1.6 g of 8-[N-(2,6-dimethylphenyl)-carbamylmethyl] nortropinone, m.p.

m.p. 204—205° C (corr.)

Analysis: Calculated for C17H0.,N2Oo: C = 71.29; H =

7.74; N = 9,787

Found: C = 71.22; H = 8.05; N = 9.72.

The oxime of 8-[N-(2,6-dimethylphenyl)-carbamylmethyl]-nortropinone was prepared by heating 4.3 g of the ketone, 4 g of hydroxylamine hydrochloride, 12 ml of pyridine and 100 ml of absolute ethanol at 100° C until a chlorine solution was obtained. The mixture was allowed to stand overnight at room temperature, heated at reflux for 1 hour, and then concentrated in vacuo. The residue was recrystallized from water and 3.8 g of oxime was obtained, which had m.p. 198.5-201° C (corr.) after recrystallization from acetone.

Analysis: Calculated for C17H„3N3O0: C = 67.74; H =

7.69; N = 13.94. Found: C = 67.50; H = 7.56; N = 13.87.

Preparations for local anesthesia can be prepared by using the new N'-[N-(monocarbocyclic aryl)carbamyl-lower-alkyl]-1,5-imlnocycloalkane and -alkene substituents and salts thereof together with pharmacological binders. By a pharmacological binder is meant here any substance that can give the preparations a suitable shape or consistency. If it concerns liquid preparations that are to be used locally or injected, the binder is water, to which additional substances may have been added for stabilization and similar purposes, e.g. methyl p-hydroxybenzoate, chlorobutanol, sodium ubisulphite, sodium chloride, dextrose, inositol, etc., or contain pharmacodynamically active substances such as e.g. a vasoconstricting substance, for example epinephrine, phenylephrine. For ointment preparations, additives such as lanolin, mineral oil, wool grease, etc. are preferably used. As an example of a preparation for local anesthesia according to the invention, the following can be mentioned: an injectable aqueous preparation contains in each ems 10 mg 8-[N-(2, 6-dimethylphenyl)carbamylmethyl]-nortropane hydrochloride, 7 mg sodium chloride and 1 mg methyl parahydroxybenzoate; an injectable aqueous preparation contains per cm3 20 mg 8-[N-(2,6-dimethylphenyl)carbamylmethyl]-nortropane hydrochloride, 0.01 mg epinephrine hydrochloride, 6 mg sodium hydrochloride and 1 mg methyl para-hydroxybenzoate; an aqueous preparation for local use may contain 10 mg of 8-[N-(2,6-dimethylphenyl)-carbamylmethyl]-nortropane hydrochloride, 4 mg of chlorobutanol and distilled water to 1 ml of solution; an ointment may contain 1% 8-[N-(2,6-dimethylphenyl) carbamylmethyl]-nortropane dissolved in petrolatum.

Claims (1)

1. Process for the production of locally anesthetically effective monocarbocyclic arylcarbamyl-alkylamines or acid addition salts or quaternary ammonium salts thereof with the general formula (I) where R, R' and R" mean hydrogen, lower alkyl, lower alkoxy or halogen radicals, Y means a lower alkylene radical, n et