US3862321A

US3862321A - Acyl xylidide local anaesthetics

Info

Publication number: US3862321A
Application number: US447680A
Authority: US
Inventors: Herbert John Frederich Adams; George Herbert Kronberg; Bertil Herbert Takman
Original assignee: Astra Pharmaceutical Products Inc
Current assignee: Astra USA Inc
Priority date: 1971-07-19
Filing date: 1974-03-04
Publication date: 1975-01-21
Anticipated expiration: 1992-01-21

Abstract

The 2-alkyl-2-alkylamino-2'',6''-acetoxylidide compounds are useful as long lasting local anaesthetics.

Description

Uited States Adams et a1.

ACYL XYLIDIDE LOCAL ANAESTHETICS Inventors: Herbert John Frederich Adams;

George Herbert Kronberg; Bertil Herbert Takman, all of Worcester,

Mass.

Assignee: Astra Pharmaceutical Products, Inc.,

Worcester, Mass.

Filed: Mar. 4, 1974 Appl. No.: 447,680

Related U.S. Application Data Continuation-impart of Ser. No. 164,022, July 19, 1971, Pat. No. 3,812,147, which is a continuation-in-part of Ser. No, 100,777, Dec. 22, 1970, abandoned.

U.S. CL. 424/274, 424/324 Int. Cl A6lk 27/00 Field of Search 424/274, 324

[451 Jan. 21, 1975 OTHER PUBLICATIONS Liifgven et a1., Svensk, Kem. Tid., V01. 58, (1946), pp. 206-217.

Schonenberger et aI., Archiv der Pharmazie, 301Bd, 1968/10 pp. 780785.

Primary Examiner.1erome D. Goldberg Attorney, Agent, or Firm-Brumbaugh, Graves, Donohue & Raymond [57] ABSTRACT The 2-alkyl-2-alkyIamin0-2,6'-acetoxylidide pounds are useful as long lasting local anaesthetics.

16 Claims, No Drawings com- ACYL XYLIDIDE LOCAL ANAESTHETICS ethyl, propyl or butyl; R together with R is tetramethylene; the number of carbon atoms in R, R and R is This application is a continuation-in-part of our US. totally at least six; or the pharmaceutically acceptable application Ser. No. l64,022, filed July 19, 1971 now salts thereof. These compounds are racemic com- U.S. Pat. No. 3,812,247, which in turn is a continua- 5 Pounds and hence the local anaesthetic 0t lfoptical tionqmpan f our g application NQ 100 777 isomers are included within the scope of the present infiled Dec. 22, l970, now abandoned. vention- The present invention relates to 2-alkyl-2- Representative compounds include the following: 2- alkylamino-2',6-acetoxylidide local anaesthetic comdiethylamino-2',6-n-butyroxylidide, which can be alpounds. ternatively named 2-ethyl-2-diethylamino-2,6'-

Two acylxylidide local anaesthetic compounds which acetoxylidide, having the formula are commercially available are N-n-butylpipecolyl-2,6-

xylidide or bupivacaine sold under the trademark CH Marcaine having the structural formula z a CH CH CH CHJ NH-C-CH-N cn U l cu cn .H l CH 0 cn cn 1- N i NH-t 2-(N-ethyl-n-propylamino)-2,6-n-butyroxylidide,

g i which can be alternatively named 2-ethyl-2(N-ethyl-npropylamino)-2,6-acetoxylidide, having the structural formula i "r .and diethylaminoaceto-2,6-xylidide or w-diethylamino- 2,6-dimethyl-acetanilide or lidocaine sold under the I CHZCHB trademark Xylocaine having the structural formula k, czis 3.0 J/ l i v CHgCHgCHg o cn ca 2. C mus-ca e] H3 H O CHZCHa 2-d1ethylammo-2,6n-valeroxylid1de, which can be alternatively named 2-n-propyl-2-diethylamino-2',6'-

CH3 acetoxylidide, having the structural formula However, while bupivacaine or Marcaine is a long last- 2 CH ing local anaesthetic, it has the drawback of being irri- 4O z a tating to tissue and while lidocaine or Xylocaine is not irritating to tissue, it has the drawback of not being a NH'C CH I\ long lasting local anaesthetic. i CH CH3 2 Other local anaesthetics which are commercially available include a-propylaminopropiono-2-toluidide or prilocaine sold under the trademark Citanest; -py -M- fl or pyrrocaine sold 2-pyrrolidino-2',6-n-butyroxylidide, which can be alunder the trademarks Endocaine" and Dynacaine; ternatively named 2 h 1 2 1idi 2Q6- and N-methylpipecolyl'z,6'Xy1idide mepivacatne acetoxylidide, having the structural formula sold under the trademark Carbocaine. However, these local anaesthetics are of short action. CH

It is, therefore, the principal object of the present in- 4 CH -CH vention to provide compounds which generally have the combined properties of long lasting local anaes- C- thetic effect or high local anaesthetic activity, a satisl factory low level of tissue irritation and a satisfactory low acute toxicity.

The compounds of the present invention are the 2- I alkyl-2-alkylamino-2,6'-acetoxylidide local anaes- 2-(N-ethyl-n-butylamino)-2',6-n-butyroxylidide,

I O CIIZCHQCHQ 45 3 I CH2CH2 'O CHzC-Ha thetic compounds having the structural formula which can be alternatively named 2-ethyl-2-(N-ethyl-nbutylamino)-2,6'-acetoxylidide, having the structural CH3 formula R2 p 3 1 NHC-CHN cu ca i A ii 1 2 R NH-CCHN (H .3 CHZCHZCHZCHQ wherein R is ethyl, propyl or butyl; R and R may be 0 CH CH the same or different alkyl radicals and are methyl, 3

3 2-dimethylamino-2,6-caproylxylidide, which can be alternatively named 2-n-butyl-2-dimethylamino-Z,6- acetoxylidide, having the structural formula and 2-pyrrolidino-2',6'-n-valeroxylidide, which can be alternatively named 2-n-propyl-2-pyrrolidino-2',6'-

acetoxylidide, having the structural formula CH CH -CH NHC-CI-1N (L -CH o cn ca ca The compounds of the invention can be prepared in accordance with the following partial class reactions:

n 1 ""4 o R where R, R and R are as stated above and X is a bromine or a chlorine atom. More detailed and other procedures of preparation are give in the representative examples hereinafter.

The racemic compounds may be resolved into their 6 and l-optical isomers by treatment with land 6 EXAMPLE 1 This example illustrates the preparation of 2- diethylamino-2',6-n-butyroxylidide or a-(diethylamino)-n-butyro-2,6-xylidide. (a-Bromo-n-butyryl chloride) Redistilled thionyl chloride (2.40 moles) was added to a-bromo-n-butyric acid (1.20 moles) in a 1,000 ml. flask attached to a reflux condenser and drying tube. The mixture was heated to reflux for 5 hours. Excess thionyl chloride was distilled off with the bath temperature up to 120C. The reaction mixture was kept at 25-30C. for 1 hour at water pump vacuum, whereafter the bath temperature was raised slowly to 80C., at which point the a-bromo-n-butyryl chloride started distilling; bp. 4850C.; yield: 1.10 moles (92%). A product sufficiently pure for the following reaction was obtained by omitting the vacuum distillation and allowing a stream of dry argon (or nitrogen) to pass through the a-bromo-n-butyryl chloride at 80-100C. for 1.5-2 hours after the main bulk of thionyl chloride had been distilled off. I

(a-Bromo-n-butyryl-2,6-xylidide) a-Bromo-nbutyryl chloride (1.005 moles) was added to a cold mixture (510C.) of 2,6-xylidine (0.92 mole) and glacial acetic acid (814 ml.) in a 4 liter bottle, quickly mixed, and quickly followed by a cold solution of sodium acetate trihydrate (315.6 g.) in water 1,610 ml.). The bottle was closed and shaken for minutes. The precipitate was filtered and washed several times by slurrying in water to remove the acetic acid as efficiently as possible. It was then dried in air or in vacuum; m.p. 198200C.; yield: 0.74 mole (80%). Calculated for C H BrNO: C 53.3, H 5.97, Br 29.6. Found: C 53.3, H 5.79, Br 29.7.

[a-(Diethylamino)-n-butyro-2,6-xylidide] a-Bromo-n-butyryl-2,6-xylidide (0.0148 mole), diethylamine'(0.0444 mole), and anhydrous benzene (25 ml.) were heated at C. for 15 hours in a pressure vessel. After cooling, the diethylammonium bromide was filtered off and the benzene solution extracted with three 25 ml. portions of l M hydrochloric acid. The acid extract was washed with 25 ml. of ether and brought up to pH 10 with 7 M sodium hydroxide and extracted with four 25 ml. portions of ether. The ether extract was dried over anhydrous sodium sulfate, filtered and the ether evaporated under vacuum giving a-(diethylamino)-n-butyro-2,6-xy1idide (0.00499 mole, 33.7%) as a waxy solid. This was converted to its hydrochloride salt with ethereal hydrogen chloride, and the salt was recrystallized three times from a mixture of absolute ethanol and ether; m.p. 224.5-226C. (decomp.). Calculated for C H ClN O: C 64.3, H 9.11, N 9.37. Found: C 64.4, H 9.12, N 9.39. I.r. (KBr disc, hydrochloride) #3175 (s, NH amide), 2980 and 4H, NCH C1;1 3.25 (t, 1H, COCH), 6.98 (s, 3H, Ph), 8.73 (s broad, 1H, NHCO). A gas chromato- (m, 2H, CHCH CH 2.18 (s, 6H, Ph CH 2.68 (q,

graphic analysis of the compound showed the presence of one single peak.

EXAMPLE 2 This example illustrates the preparation of 2-(N- ethyl-n-propylamino)-2',6-butyroxylidide or a-(N- ethyl-n-propylamino)-n-butyro2,6-xylidide. (a-Bromom-butyryl-Z,6-xylidide) This compound was prepared as described in Example 1. (a-lodo-n-butyryl-2,6-xylidide) a-Bromo-n-butyryl- 2,6-xylidide (224.7 g., 0.832 mole), powdered potassium iodide (191.2 g., 1.15 moles) and anhydrous methanol (1,200 ml.) were mixed in a 3,000 ml. flask equipped with reflux condenser, mechanical stirrer and heating mantle. After refluxing for 3 hours, the mixture was allowed to cool for 30 minutes with continued stirring, transferred with stirring to a beaker containing 2.5 liters distilled water and left for 1 hour. The precipitate was filtered and pressed as dry as possible. It was then transferred back to the beaker and carefully stirred with circa 1.5 liters distilled water and filtered again. This procedure was repeated until the filtrate was free from bromide and iodide ion. The precipitate was then dried in air and/or in a desiccator. Yield: 243 g. mp 220-222C. (decomp.).

The obtained preparation was almost colorless. Recrystallized from 95% ethanol the product melted at 223.5C. under decomposition.

The uncrystallized product contains some of the bromo compound but was sufficiently pure for the following step. [a-(n-propylamino)-n-butyro-2,6-xy1idide] Method a. n-propylamine (67.9 g., 1.15 moles) and a-iodo-n-butyryl-2,6-xylidide (121.5 g., 0.383 mole) were mixed with anhydrous benzene (1,220 ml.) in a flask equipped with reflux condenser, mechanical stirrer and heating mantle and refluxed for 8 hours. The light yellow solution was filtered from a yellow precipitate which was washed thoroughly with ether. The precipitate (no C=O band in ir) was discarded. The filtrate and washings were combined and evaporated leaving a yellow residue (143.4 g.).

The residue was treated with 380 ml. 1 M hydrochloric acid. An insoluble solidwas filtered off and washed with ether. The acid filtrate was extracted with ether and an additional precipitated solid was filtered off and combined with the primarily obtained insoluble solid. The weight of the combined solid fractions was 156.2

g. (I). The acid filtrate (11) was washed with four additional portions of'ether. The solid fraction I was refluxed with anhydrous benzene. filtered, and washed with hot benzene and ether. The combined benzene and ether extracts from these operations contained 6.8 g. residue and was discarded. The solid fraction 1 and the acid solution 11 were combined and based out with 7 M NaOH and the freed base was extracted into ether. After drying over anhydrous sodium sulfate the ether extract was filtered and evaporatedyielding 93 g. of a partly solidifying maroon-colored residue.

6 This residue was dissolved in ml. of ether in a separatory funnel and equilibrated with 200 ml. phos phate buffer so that the pH at equilibrium was 7.3.

Keeping the pH at 7.3 the buffer solution was extracted three more times with 80 ml. portions of ether.

The ether extracts yielded 79.2 g. of a base that contained mainly the desired compound and which was sufficiently pure for the next step.

From the buffer solution 6.3 g. of an oil could be obtained on raising the pH -to 11 and extracting with ether. This fraction contained mainly theB-substituted isomer, and was discarded.

Method b. a-Bromo-n-butyryl-Z,6-xylidide (63.1 millimoles), n-propylamine (254 millimoles), sodium iodide (63.1 millimoles), and absolute ethanol (180 ml.) were refluxed for. 6.5 hours. The alcohol was evaporated in vacuo and the residue was mixed with 0.5 M HC] (200 ml.). The suspension was washed with two ml. portions of ether, the pH adjusted to 11 with 7 M NaOH and the mixture extracted three times with 100 ml. portions of ether. After drying over anhydrous sodium sulfate the ether was evaporated leaving a residue of the amine. Yield: 5l.0'mi11imo1es (81%); The hydrochloride hydrate was prepared from the base with ethereal hydrogen chloride and addition of water. Recrystallized from ethanol/ether it melted at l99l99.5C. Calculated for the base (C, H N O): C 72.5, H 9.74, N 11.3. Found: C 72.5, H 9.81, N 11.2. [a-(N-ethyl-n-propylamino)-n-butyro-2,6-xylidide]-- a-(n-propylamino)-n-butyro-2,6-xy1idide (0.243 mole) and freshly distilled diethyl sulfate (1.6 moles) were mixed in a flask equipped with reflux condenser, drying tube and stirrer. The mixture was stirred for 5 hours at 90C. After cooling, water ml.) was added with stirring for 15 minutes followed by 4 M HCl (1 10 ml.). The solution was washed with ether (3X100 ml.) and made alkaline with 7 M NaOH to pH 10-1 1. The freed base was taken up in ether (3x100 ml.); the extracts were dried over sodium sulfate, filtered and evaporated. The residue was dissolved in absolute ether (200 ml.) and the' hydrochloride prepared by addition of ethereal hydrogen chloride. The precipitate was filtered, washed with ether, and recrystallized twice from absolute ethanol/ether and from isopropanol/isopropylether; m.p. 203-203.5C.; yield: 0.126 mole (52%). Calculated for C H ClN O:C 65.3, H 9.34, C1 11.3. Found: C 65.2, H 929, C1 11.3. l.r. (KBr disc, hy-

. drochloride) 3175 (s, amide NH), 2970 and 2940 (s,

CH and CH 2580 (s, NH), 2505 (5, NH*), 1680 (s, amide 1), 1595 (w, Ph), 1531 (s, amide 11), 1474 (s), 1227 (s, amide 111), 778 (s, Ph 3 adjacent hydrogens out of plane) cm". N.m.r. (CDCl base) 81.06 (t,

CHgCfia), 1.26 (t, CH clj [9H for the two triplets], 1.58-2.48 (m, 4H, CH CH 2.53 (s, 6H, PhCH 2.823.30 (m, 4H, NCH 3.72 (t, 1H, COCH), 7.98 (s, 3H, Ph). A gas chromatographic analysis showed 7 one single peak.

EXAMPLE'3 The racemiccompound of Example 2 was resolved into the 8 and loptical isomers by the following pro cedure:

' The racemate of a-(N-ethyl-n-propylamino)-nbutyro-2,6-xylidide base (9.73 g., 0.3519 mole) was dissolved in a mixture ofl-tartaric acid (5.28 g., 0.3519 mole) and 19.5 ml. water by gentle heating. After filtering, the solution was cooled and left at 4C. The crystals formed were filtered cold. The mother liquor was concentrated to about half its volume and a second crop was obtained. The combined crops (1) were recrystallized repeatedly from water until constant optical rotation was obtained [a] 8.3. The mother liquor was made alkaline with 7M sodium hydroxide and extracted with ether. The ether was evaporated and 3.18 g. (0.0115 mole) residual base was obtained which was dissolved in a solution of -tartaric acid (1.73 g., 0.0115 mole) in 6.4 ml. water with heating. From the cold solution (4C.) crystals (11) were obtained which were recrystallized repeatedly from water until constant rotation was obtained, [a] 8.6. The bases were liberated from the two tartrates with sodium hydroxide in water. The bases from (1) and (11) had specific rotation of +34.1 and -32.8, respectively. The rotation of their hydrochlorides were +6.2 and -6.2, respectively, after recrystallization from abs. ethanol ether. Their melting points were identical, 184185C.

The racemic compounds of Examples 1 and 4-8 can be resolved into the 6- and 1- optical isomers thereof by a procedure similar to the one of Example 3.

EXAMPLE 4 This example illustrates the preparation of 2- diethylamino-2',6'-n-valeroxylidide. 2-Bromo-2,6'-n-valeroxylidide In a 2 liter bottle were mixed 2,6-xylidine (0.347 mole) and glacial acetic acid (310 ml.). The mixture was cooled to 12C. and 2-bromo-n-valeryl chloride (0.349 mole) was added rapidly. After quick mixing a precooled (5C.) solution of sodium acetate trihydrate (85 g.) in water (340 ml.) was immediately added and the mixture was shaken for circa minutes. The solid was filtered and washed carefully and repeatedly with water until the filtrate was free from bromide. After drying in a desiccator over potassium hydroxide flakes the solid (0.345 mole) melted at 189-190.5C. After recrystallization from 95% ethanol the melting point of the colorless crystals was 190-190.5C. Yield: 65-78%. Calculated for C H BrNOz C 54.9, H 6.38, Br 28.1. Found: C 54.9, H 6.33, Br 28.2. 2-Diethylamino-2',6-n-valeroxylidide A mixture of 2-bromo-2',6'-n-valeroxylidide (0.176 mole), diethylamine (0.528 mole), and benzene (125 ml.) was placed in a pressure vessel and heated to 100C. for hours. After cooling, the dark brown content was filtered and the solid (23.2 g. of diethylammonium bromide) washed carefully with benzene. The filtrate was extracted with 4N hydrochloric acid (3X50 ml.). the acid extract washed with ether (3X50 ml.), and based out with 7N sodium hydroxide under cooling and stirring and in the presence of ether (100 ml.). After two further extractions with ether (2X50 ml.) the combined ether extracts were dried (Na SO and the ether evaporated leaving 16.5 g. of residue. The hydrochloride was prepared from the residue by dissolving it in ether and adding ethereal hydrogen chloride. The hydrochloride was recrystallized from abs. ethanol: ether (3:5) twice, m.p. 205206C. Calculated for C H C1N O: C 65.3, H 9.34, N 8.95. Found: C 65.2, H 9.49, N 9.15. Only one distinct peak was obtained on gas chromatography of the salt. l.r. (KBr disc, hydrochloride): 3170 (mw, NH amide); 2968 and 2930 (m, CH and CH 2560 (m, NH); 1677 (s, amide 1); 1593 (w, Ph); 1528 (s, amide I1); 1472 and 1433 (ms); 1230 (mw, amide I11); 775 (m, 3 adjacent Ph hydrogens out of plane.

EXAMPLE 5 This example illustrates the preparation of 2- pyrrolidino-2 ,6 '-n-butyroxylidide. 2-Pyrrolidino-2,6'-n-butyroxylidide A mixture of 2-bromo-2',6'-butyroxylidide (0.0463 mole). Plrrolidine (0.13 g. mole) and benzene (100 ml.) was refluxed for 21 hrs. The solvent and excess pyrrolidine were evaporated in vacuo leaving a partly solidifying residue that was dissolved in 1 N hydrochloric acid (125 ml.). The acid solution was washed with ether (2X50 ml.) whereafter it was made alkaline with 7 N sodium hydroxide and extracted with ether (3X50 ml.). The ether extract was dried (Na SO.,) and the solvent evaporated in vacuo. The hydrochloride was prepared by dissolving the residue in ether and adding a sufficient amount of gaseous hydrogen chloride; yield 0.0414 mole. After two recrystallizations from 95% ethanol: ethyl acetate (1:1) the colorless crystals melted at 23 8240C. Calculated for C H N- oclz C 64.7, H 8.49, Cl 11.9. Found: C 64.9, H 8.59, C] 12.1. l.r. (KBr disc, hydrochloride): 3450 (m, broad); 3175 (ms, amide NH); 2965 and 2927 (ms, CH and CH 2670, 2630, and 2600 (ms); 2475 (mw, NH*); 1680 (s, amide I); 1529 (w, Ph); 1525 (s, amide 11); 1469 (ms); 1227 (m, amide 111); 781 (ms, 3 adjacent Ph hydrogens out of plane).

EXAMPLE 6 This example illustrates the preparation of 2-(N- ethyl-n-butylamino)-2,6'-n-butyroxylidide.

' 2-n-Butylamino-2',6'-butyroxylidide A mixture of 2-iodo-2,6'-butyroxylidide (0.0315 mole), nbutylamine (0.0945 mole) and anhydrous benzene 100 ml.) was refluxed for 5 hrs. After cooling, the benzene and excess n-butylamine were evaporated in vacuum. The residue was taken up in l N hydrochloric acid, washed with ether (3X25 m1.), filtered, made alkaline to a pH of 9 with 7 N sodium hydroxide and extracted with ether (4X25 ml.). The ether extract was dried (Na SO and the ether was then evaporated in vacuo leaving a colorless oil (0.0153 mole). (This oil is sufficiently pure for the ethylation step described below.) A hydrochloride was prepared from the oily base in anhydrous ether by addition of an ethereal hydrogen chloride solution. The formed product was not crystallizing readily from a number of solvents. On dissolving in water, crystals appeared on standing. The formed hydrochloride hydrate was recrystallized from aqueous ethyl acetate, m.p. 92-95C. Calculated for C H ClN,O H 0: H 0 5.71. Found: 5.73 (Karl Fischer). A sample was dried at high vacuum and elevated temperature. Calculated for C H CIN O: C 64.3, H 9.1 1, C1

11.9. Found: C 64.1, H 9.26, Cl 11.8.

2-(N-ethyl-n-butylamino)-2',6-n-butyroxylidide A mixture of 2-n-butylamino-2,6'-butyroxylidide [the oily unpurified base (0.0153 mole) mentioned above] and diethyl sulfate (0.0996 mole) was heated at C. for 5 hrs. After cooling, the clear amber-colored solution was mixed with 10 ml. of water, stirred for 15 min. and mixed with 10 ml. of 4 N hydrochloric acid. The acid solution was washed with ether allowing the phases to separate completely, the upper ether layer being discarded each time. The pH was adjusted to l 1 with 7 N sodium hydroxide and the separating base taken up in ether (4 X 30 ml.). After drying (Na SO.,) the ether was evaporated leaving a residue of crude base (0.0395 mole). The hydrochloride was prepared by dissolving the residue in anhydrous ether and adding ethereal hydrogen chloride to the solution. Recrystallized from abs. alcohol: ether, colorless crystals were obtained melting at 202.5-204.5C. Calculated for C H ClN O: C 66.1, H 9.56, Cl 10.8. Found: C 66.1, H 9.71, Cl 11.1. IR. (KBr disc, hydrochloride): 3160 (ms, amide NH); 2960 (s) and 2890 (ms)(CH and CH 2615-2595 (m, broad); 2505 (m, NH); 1680 (s, amide I); 1594 (w, Ph); 1530 (s, amide 11); 1470 (s); 1228 (m, amide 111); 781 (m, 3 adjacent Ph hydrogens out of plane).

EXAMPLE 7 This example illustrates the preparation of 2- dimethylamino-2',6-caproylxylidide. 2-Bromo-2,6'-caproylxylidide A mixture of 2,6- xylidine (0.125 mole) and glacial acetic acid (1 15 ml.) was cooled to 10C. in a 1 liter bottle and 2- bromocaproyl bromide (0.136 mole) was added and mixed rapidly. As fast as possible this was followed by a cool (50C.) solution of sodium acetate trihydrate (45 g.) in water (190 ml.). The mixture was shaken for 45 min. and filtered. The precipitate was washed carefully and repeatedly with water until free from bromide ions. It was then dried in a desiccator over potassium hydroxide flakes and recrystallized from methanol: water (approx. :1) twice; m.p. 167169C. Yield: 67%. This material was sufficiently pure for the subsequent reaction. The pure compound (one further recrystallization) had a m.p. of 168.5-169C. Calculated for C H BrNO: C 56.4, H 6.76, Br 26.8. Found: C 56.2, H 6.40, Br 25.9.

Z-Dimethylamino-Z',6-caproylxylidide A mixture.

of 2-bromo-2,6-caproylxylidide (0.110 mole), dimethylamine (0.356 mole) and benzene 177 ml.) were heated in a pressure vessel for 22 hrs. at 100C. After cooling the reaction mixture was filtered. The weight of the obtained dimethylammonium bromide indicated that 97% of the bromo compound had reacted. The filtrate was extracted with 4 N hydrochloric acid (1X50+2 25 ml.), the acid solution based out to pH 11 with 7 N sodium hydroxideand extracted with ether (3X50 ml.). The combined ether extracts were dried (Na SO and evaporated in vacuo. From the residue the hydrochloride was prepared with etherealhydrogen chloride. It was recrystallized from abs. alcohol: ether melting at 193.5194.5C. Calculated for C H CIN O: C 64.3, H 9.10, N 9.37, Cl 11.9. Found: C 64.2, H 9.04, N 9.52, Cl 12.0. l.r. (KBr disc, hydrochloride): 3185 (m, amide NH); 2950 and 2920 (ms-m, CH and CH 2450 (ms, NH+); 1682 (s, amide I); 1591 (w, Ph); 1530 (s, amide 11), 1470 (s); 1236 (mw, amide I11); 776 (m, 3 adjacent Ph hydrogens out of plane).

EXAMPLE 8 This example illustrates the preparation of 2- pyrrolidine-2',6'-n-valeroxylidide. 2-Iodo-2,6'-n-valeroxylidide A mixture of 2-bromo- 2,6'-n-valeroxylidide (0.137 mole), potassium iodide (1:8) twice, yielding colorless crystals (0.0992 mole) (0.274 mole) and dry methanol (375 ml.) was refluxed under stirring for 3 hrs. After cooling, 1 liter of water was added to the yellow-colored reaction mixture and it was left with stirring for 15 min. The precipitate was filtered, washed repeatedly with water until the filtrate was free of halogenides, and dried. After recrystallization from ethanol it melted at 1'96.5197.5C.; yield 0.105 mole of a product sufficiently pure for the next synthetic step. Another recrystallization brought the m.p. to 197198C. Calculated for C H lNO: C

47.1, H 5.48, 138.3. Found: C 47.3, H 5.36, I 38.2.

2-Pyrrolidino-2,6-n-valeroxylidide A mixture of 2-iodo-2,6n-valeroxylidide (0.0754 mole), pyrrolidine (0.226 mole) and benzene (65 ml.) was heated in a pressure vessel for 24 hrs. at C. After cooling, the benzene and excess pyrrolidine were evaporated in vacuo. The residue was stirred with water ml.) for 30 min. and filtered. To the filtrate 7 N sodium hydroxide was added (pH 11) with stirring and after 30 min. the solid base was filtered, washed carefully and repeatedly with water and dried in vacuo. The crude base 14 g.) was recrystallized from aqueous ethanol to constant m.p. (l26127.5C.); yield 4.9 g. From the mother liquo'rs another 2.7 g. were obtained. Total yield: 37%. Calculated for C H N O: C 74.4, H 9.55, N 10.2. Found: C 74.1, H, 9.66, N 10.4. Ir. (KBr disc, base): 3210 (s, NH amide); 2933 (s), 2915 (ms) (CH and CH 1645 (s, amide I); 1593 (w, Ph); 1529 (s, amide II): 1478 and 1465 (ms); 770 (s, 3 adjacent Ph hydrogens out of plane).

EXAMPLE 9 This example illustrates, pharmaceutical compositions. Solutions containing 0.25, 0.50, 0.75 and 1.0% 2-(N-ethylpropylamino)-2',6-butyroxylidide hydro chloride without added vasoconstrictor. pH 3.5-4.5.

Amount (g) Component 0.25 0.50 0.75 1.0

2-(N-Ethylpropylamino)- 2.50 5.00 7.50 10.00

hydrochloride Sodium chloride USP XVlll 8.53 8.07 7.70 7.10

Hydrochloric acid, 2N Sodium hydroxide, 2N Water for injection, USP XVlll Sufiicient amount to make If necessary to adjust pH do The active ingredient of the solutions above can be replaced by 2-diethylamino-2',6-n-valeroxylidide hydrochloride.

EXAMPLE 10 2',6'-butyroxylidide,

hydrochloride -Continued Amount (g) Component 0.25% 0.50% 0.75% 1.0%

Sodium chloride, USP XVIII 8.53 8.07 7.70 7.10 Epinephrine, USP XVIII 0.0050 0.0050 0.0050 0.0050 Sodium metabisulfite 0.50 0.50 0.50 0.50 Sodium hydroxide, 2N If necessary to adjust pI-I Hydrochloride acid, 2N 0. Water for injection. USP XVIII Sufficient amount to make 1000 ml.

The active ingredient of the solutions above can be butyromesidide having the following structural formula:

CH CH n e NH-C-CH-N ll 1 CHgCHa O CH CH Tables I through V contain comparative data on the duration of several of these local anaesthetic compounds, Table VI contains comparative data on the degree of tissue irritation of several of these local anaesthetic compounds, Tables VII and VIII contain comparative data on the acute toxicity of several of these local anaesthetic compounds, Tables IX through XI contain data on clinical trials of Compound B in man. and Table XII contains comparative tissue distribution data of two of these local anaesthetic compounds in a representative animal species.

TABLE I Rat Sciatic Nerve Blocks Duration in Minutes 1 Standard Deviation Conc as Base A B C D E F G H 0.125 156132 156141 81122 1111 5 117111 9615 131116 96122 0.25 235112 222154 96116 148119 123119 11619 179118 117111 0.5 29716 279116 114123 160127 140112 135118 236138 126113 1.0 30815 3131 9716 191157 179127 178118 3days 146119 2.0 172 137 287 186 268 136 180143** 280 142* Conc as Base X Y Z 0.125 121132 101115 0.25 175116 102115 114114 0.5 212134 123110 118115 1.0 213 162139 126121 2.0 185123 146118 All solutions contained l:l00,000 epinephrine. Test method given in Truant. A.P.: Arch. Int. Pharmacodyn. 115: 483-497 (1958), which is incorporated by reference herein. "Some animals blocked 12 hrs.

TABLE II Guinea Pig Intradermal Wheals" Duration in Minutes 1 Standard Deviation Conc. as Base A B X Y Z All solutions contained I:.O0,000 epinephrine. Test method given in Bulbring, E. and Wajda, 1.: J. Pharmacol. Exp. Therap. 85: 73-84 (1945), which is incorporated by reference herein.

TABLE 111 Peridural Anaesthesia in the Cat* Duration of Block of Support of Weight in Minutes 1 Standard Deviation All solutions contained 11100.0() epinephrine.

Test method given in Duce. B. R.. Zelechowski. K.. Camougis. G. and Smith. E. R.: Brit. J. Anaesth. 41: 579-587 (1969). which is incorporated by reference herein.

Toxic effects observed at this concentration.

TABLE VI lrritation Studies: Rabbit lntradermal Wheals Solutions did not contain epinephrine.

Test method given in Truant. A.P.: Arch. Int. Phurmucodyn. 115: 4113-497 (1958). whtch IS incorporated by reference herein.

15 TABLE vn TABLE IV Peridural Anaesthesia in the Guinea Pig* Acute Tox y in Female i Duration of Block of Support of weight Com- LD and 95% Fieller Confidence Limitszmglkg as Base in Minutes 1 Standard Devimion pound lntraperitoneal Intravenous Conc. I as Base E G X Y A 54(46-117) 9.4(8.2-11) B 62(53-82) 5.8(5.1-6.5) 7 C I -15.9(l4.0l8.6) O...5 39. 7 4618 38-7 10 D 6(54 6.7) 0.5 5517 101121 59112 1412 E (4148) 1.0 6815 8918 2116 G 37(28 49) H 11.3(9.2-l3.9) All solutions contained 11100.000 epinephrine. X 40( 28-56) 6.4( 5.5-7.3) Test method given in Tan and Snow. Am. .1. Vet. Res. 29. 487 (1968), which is Y 2( incorporated by reference herein. Z 93(81-110) 9.4(8.3-10.6) "Three animals died 5 minutes post-injection and one animal did not recover from hlock. Solutions did not contain epinephrine.

TABLE v TABLE Vlll Peridural Anaesthesia in the Dog Duration of Block of Support of Weight in Minutes Conc. as Base E X Y Acute Subcutaneous Toxicity inMale and Female Rats LD and 95% Fieller Confidence Limitszmg/kg as Base 0.5 304 SEX 1.0 417 A B X 2,0 137 y Male 136( 102-172) 71153-90) All solutions contained 12100.000 epinephrine. Female 94(73-120) 124(98-160) 74(58-98) Test method given in Lebeaux. ML: Brit. J. Anaesth. :549-588 (1973) which is incorporated by reference herein. Solutions contained l:200.000 epinephrine.

TABLE IX Peridural Anesthesia in Man. Compound B. Epinephrine 1200.000. Onset and duration times in minutes 1 SD. Concn. Vol- Dose Sensory Onset Motor Onset Complete Return Number of ume ml. mg. Initial Complete Initial Complete Sensory Motor patients 0.5 20 4611.1 17113.8 10.5fl.5 17412.3 189.7fl1.0 147.81.31.61 10-16 0.5 30 4.7108 15814.1 10.85.4- 18714.6 242.l143.2 l65.0131.5 4-7 0.75 20 150 4.4109 16.3-12.0 10311.8 17.6fl. 1 256.41522 181.61391 7-8 0.75 30 225 4710.8 15.8fl.4 9.8fl.1 l4.5fl.7 243.5128.1 1955-1313 11-12 1.0 20 200 4.411.1 18.4-13.3 9.9fl.6 17.5132 285.7fl3.0 22031578 16-21 1.0 30 300 4.01.0.6 16.7131 9.8fl.1 17015.1 319.4162.8 26131663 20-23 Number of patients: The range indicates incompleteness of data TABLE X lntracestal Blocks in Man. Compound B. Epinephrine 1:200. Onset and duration times in minutes 1 SD.

Complete Return Concn. Vol- Dose Sensory Onset (sensory) Number of ume ml. mg. lnitial Complete initial Complete Patients TABLE Xl Brachial Plexus Blocks in Man. Compound B. Epinephrine 1200.000. Onset and duration times in minutes :SD.

Concn. Vol- Dose Sensory Onset Motor Onset Complete Return Number of mg. lnitial Complete initial Complete Sensory Motor Patients 0.5 lOO 3.7il.4 9113.1 3.l- *l.7 103:4.2 606.71135 57l.7il73 6-8 0.5 30 l50 3.212.] 7.2fl.4 2910.6 8.6fl.l 516.01155 475.7:140 7-l() TABLE Xll vention generally are appreciably longer lasting local anaesthetics, particularly at use concentrations of 1% A. Tissue Distribution ofB and ofXin the or 2%, than are the comparative homologous comg f 15 pounds Y and Z and yet they have a satisfactory low Drug Concentration (Mg/gm) level of tissue irritation and a satisfactory low acute Tissue B toxicity. Blood 2, 3,7 The local anesthetic compositions of the invention Brain 131 illustrated above, therefore, comprise as the active in- Heart 4.7 14.4 Fat 202 163 20 gredtent thereof a 2-alkyl-2-alkylammo-2 ,6 Muscle 2-1 acetoxylidide local anesthetic compound of the inven- B g sg g l Raios B and X the tion or a pharmaceutically acceptable salt thereof in a (Lg/gm Tissue) (fig/m1 Blood) conventional amount (e.g., a concentration of Tissue B X O.l%2.0% by weight of the carrier) sufficient to prog jg vide local anesthetic effect together with a usual non- Fm toxic pharmaceutically acceptable carrier, such as wa- Muscle ter, water-ethanol, dextrose solutions, saline solutions Methods as described by J. Keenaghan and R. Boyes in J. P. E. T. l80: 454-463 Irritation indices reported in Table VI are determined in the following manner:

Wheals are made on the shaved backs of albino rabbits by intradermal injection of aqueous solutions of the agents. Twenty-four hours later each wheal is graded for: presence and severity of erythema, presence and severity of edema, and presence or absence of necrotic tissue in the wheal. The grading is done on an arbitrary numerical scale, and a mean irritation index is calculated for all wheals at a given concentration.

The test method employed for the acute toxicity studies reported in Tables VII and VIII was as follows: Sexually mature male or female animals are used.

Animals are divided into groups of 10 and dosed with drug solution or vehicle. After being dosed, animals are observed at intervals for several hours for overt effects and fatalities. Survivors are housed as groups according to dose level and checked once daily for the duration of the study in order to determine whether or not delayed fatalities occur.

LD s and 95% Fieller confidence limits (or 95% approximate limits) are calculated by the Minimum Logic Chi Square Method of Berkson, J. Am. Stat. Assoc. 48- :565 (1953).

Surgical procedures have been performed in patients to whom compound B was administered either epidurally (Table lX), intracostally (Table X), or in the braand blends thereof. in addition, such herein exemplified local anesthetic compositions may contain a vasoconstrictor, as is well known in the art, such as epinephrine, norepinephrine, phenylephrine and levonorephrine, in conventional amounts (e.g., l:lO0,000-l 200,000).

The local anesthetic compositions may be prepared in the usual manner by dissolving-the local anesthetic compound of the invention and a vasoconstrictor, when present, in the liquid carrier.

Application of the local anesthetic compositions to animals, including humans, is accomplished, as exemplified above, in the usual manner, e.g., by infiltration or injection, using conventional total dosages (e.g.. 50-450 mg).

The above Compound B, i.e., Z-(N-ethyl-npropylamino)-2',6-n-butyroxylidide (also called W-l9053 or etidocaine or Duranest"), not only possesses the above-mentioned combination of properties, but is further characterized by the properties of rapid onset of action and low toxicity in humans as shown by clinical studies, for example, those reported in the two articles appearing at pages 407-413 and 482-494 in Anesthesia and Analgesia Current Researches, Vol. 52, No. 3, May-June, 1973, the one appearing in Brit. J. Anaesth. 45:1010-1012 (1973), and those'set forth above in Tables IX through XI which were reported or disclosed in our Belgian convention Pat. No. 776,656 issued on June 14, 1972. (The entire disclosures in these three articles and Belgian patent are hereby incorporated by reference herein.)

The data of Table Xll also demonstrates the more favorable tissue distribution of Compound B compared to the prior art Compound X, i.e., bupivacaine.

What is claimed is:

l. A local anesthetic composition comprising (a) as its active ingredient a compound having the structural formula butyroxylidide.

NH-C-CH-N l wherein R is ethyl, propyl or butyl; R and R are each separately selected from the group consisting of methyl, ethyl, propyl and butyl; R together with R is tetramethylene; the total sum of carbon atoms in R, R and R is at least six; or a pharmaceutically acceptable salt thereof in an effective amount sufficient to provide local anesthetic effect, together with (b) a nontoxic pharmaceutically acceptable carrier.

2. The composition as defined by claim 1 wherein the active ingredient is 2-diethylamino-2',6'-nbutyroxylidide.

3. The composition as defined by claim 1 wherein the active ingredient is Z-(N-ethyl-n-propylamino)-2,6-nbutyroxylidide.

4. The composition as defined by claim 1 wherein the active ingredient is 2-diethylamino-2',6'-nvaleroxylidide.

5. The composition as defined by claim 1 wherein the active ingredient is 2-pyrrolidino-2,6'-n- 6. The composition as defined by claim 1 wherein the active ingredient is 2-(N-ethyl-n-butylamino)-2',6'-nbutyroxylidide. v

7. The composition as defined by claim 1 wherein the active ingredient is 2-dimethylamino-2',6- caproylxylidide.

8. The composition as defined by claim 1 wherein the active ingredient is 2-pyrrolidino-2',6-nvaleroxylidide.

18 9. A method of inducing local anesthesia in animals, which comprises applying to the area of the body to be anesthetized a locally anesthetizing amount of a compound having the structural formula wherein R is ethyl, propyl or butyl; R and R are each separately selected from the group consisting of methyl, ethyl, propyl and butyl; R together with R is tetramethylene; the total sum of carbon atoms in R, R and R is at least six; or a pharmaceutically acceptable salt thereof.

10. The method as defined by claim 9 wherein said compound is 2-diethylamino-2',6'-n-butyroxylidide.

11. The method as defined by claim 9 wherein said compound is 2-(N-ethyl-n-propylamino)-2,6-nbutyroxylidide.

12. The method as'defined by claim 9 wherein said compound is 2-diethylamino-2',6 -n-valeroxylidide.

13. The method as defined by claim 9 wherein said compound is 2-pyrrolidino-2,6-n-butyroxylidide.

14. The method as defined by claim 9 wherein said compound is Z-(N-ethyl-n-butylamino)-2,6-

butyroxylidide.

15. The method as defined by claim 9 wherein said compound is 2-dimethylamino-2,6-caproylxylidide.

16. The method as defined by claim 9 wherein said compound is 2-pyrrolidino-2',6'-n-valeroxylidide.

UNITED STATES PATENT OFFICE (5/69) CERTIFICATE OF CORRECTION Patent No. 3,862,321 Dated January 21, 1975 Inventor(s) Adams et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 3, line 49, "give" should'read'- given Col. 5,

line 7, "N-CH CE should read N"C2CH3 Col. 7,

line 9, tartaric acid" should read B-tartaric acid Cols. 11 and 12, Table I, under the caption "G", "3 days" should read 3 days bottom of Table II, second line of footnote, "85:73-84" should read 85:78-84 Cols. l3 and 14, Table IX, the figures in the last line appearing under the caption "Motor" are illegible and should therefore read 26l.3i66.3

Signed Eur. sealed this 1st day 05 April 1".T75.

:3 Attest I C. ZLKRSE-EALL uI-II I-i RUTH iii-.303: Commissioner of Patents Arresting Officer 7 and Trademarks

Claims

2. The composition as defined by claim 1 wherein the active ingredient is 2-diethylamino-2'',6''-n-butyroxylidide.
3. The composition as defined by claim 1 wherein the active ingredient is 2-(N-ethyl-n-propylamino)-2'',6''-n-butyroxylidide.
4. The composition as defined by claim 1 wherein the active ingredient is 2-diethylamino-2'',6''-n-valeroxylidide.
5. The composition as defined by claim 1 wherein the active ingredient is 2-pyrrolidino-2'',6''-n-butyroxylidide.
6. The composition as defined by claim 1 wherein the active ingredient is 2-(N-ethyl-n-butylamino)-2'',6''-n-butyroxylidide.
7. The composition as defined by claim 1 wherein the active ingredient is 2-dimethylamino-2'',6''-caproylxylidide.
8. The composition as defined by claim 1 wherein the active ingredient is 2-pyrrolidino-2'',6''-n-valeroxylidide.
9. A method of inducing local anesthesia in animals, which comprises applying to the area of the body to be anesthetized a locally anesthetizing amount of a compound having the structural formula
10. The method as defined by claim 9 wherein said compound is 2-diethylamino-2'',6''-n-butyroxylidide.
11. The method as defined by claim 9 wherein said compound is 2-(N-ethyl-n-propylamino)-2'',6''-n-butyroxylidide.
12. The method as defined by claim 9 wherein said compound is 2-diethylamino-2'',6''-n-valeroxylidide.
13. The method as defined by claim 9 wherein said compound is 2-pyrrolidino-2'',6''-n-butyroxylidide.
14. The method as defined by claim 9 wherein said compound is 2-(N-ethyl-n-butylamino)-2'',6''-butyroxylidide.
15. The method as defined by claim 9 wherein said compound is 2-dimethylamino-2'',6''-caproylxylidide.
16. The method as defined by claim 9 wherein said compound is 2-pyrrolidino-2'',6''-n-valeroxylidide.