US3812147A - Acylxylidide local anaesthetics - Google Patents

Abstract

THE 2-ALKYL-2-ALKYLAMINO - 2'',6'' - ACETOXYLIDIDE COMPOUNDS ARE USEFUL AS LONG LASTING LOCAL ANAESTHETICS.

Description

United States Patent Us. (:1. 260-3263 Claims ABSTRACT OF THE DISCLOSURE The 2-alkyl-2-alkylamino 2',6 acetoxylidide compounds are useful as long lasting local anaesthetics.

This application is a continuation-in-part of our US. application Ser. No. 100,777, filed Dec. 22, 1970, now abandoned.

The present invention relates to 2-alkyl-2-alkylamino- 2',6-acetoxylidide local anaesthetic compounds.

Two acylxylidide local anaesthetic compounds which are commercially available are N-n-butylpipecolyl- 2,6- xylidide or bupivacaine sold under the trademark Marcaine having the structural formula O C H:

and diethylaminoaceto-2,6-Xy1idide or w diethylamino-Z, 6-dimethyl-acetanilide or lidocaine sold under the trademark Xylocaine having the structural formula CHzCHa CHzCHs CH3 However, while bupivacaine or Marcaine is a long lasting local anaesthetic, it has the drawback of being irritating to tissue and while lidocaine or Xylocaine is not irritating to tissue, it has the drawback of not being a long lasting local anaesthetic.

Other local anaesthetics which are commercially available include a-propylaminopropiono-Z-toluidide or prilocaine sold under the trademark Citanest; a-pyrrolidinoaceto-2,'6-xylidide or pyrrocaine sold under the trademarks Endocaine and *Dynacaine; and N-methylpipecolyl-2,6-xylidide or mepivacaine sold under the trademark Carbocaine. However, these local anaesthetics are of short action.

It is, therefore, the principal object of the present invention to provide compounds which generally have the combined properties of long lasting local anaesthetic effect or high local anaesthetic activity, a satisfactory low level of tissue irritation and a satisfactory low acute toxicity.

The compounds of the present invention are the 2- alkyl-2-alkylamino-2',6' acetoxylidide local anaesthetic compounds having the structural formula wherein R is ethyl, propyl or butyl; R and R may be the same or diiferent alkyl radicals and are methyl, ethyl,

propyl or butyl; R together with R is tetramethylene; the number of carbon atoms in [R R and 'R is totally at least six; and the pharmaceutically acceptable salts thereof. These compounds are racemic compounds and hence the local anaesthetic dor l-optical isomers are included within the scope of the present invention.

Representative compounds include the following: 2- diethylamino-Z,6'-n-butyroxylidide, which can be alternatively named 2-ethyl-2-diethylamino-2',6'-acetoxylidide,

having the structural formula CHzCHa NHCOHN z 2-(N-ethyl-n-propylamino)2',6-n-butyroxylidide, which can be alternatively named 2-ethyl-2(N-ethyl-n-propylamino)-2',6'-acetoxylidide, having the structural formula Z-diethylamino-Z,6'-n-valeroxylidide, which can be alternatively named 2-n-propyl-2-diethylamino-2',6'-acetoxy1- idide, having the structural formula 2-pyrrolidino-2',6'-n-butyroxylidide, which can be alternatively named 2-ethyl-2-pyrrolidino-2,6'-acetoxylidide, having the structural formula /CHa-CH I J) l CHr-CHI CH: c aGHz 2 (N ethyl-n-butylamino)-2',6'-n-butyroxylidide, which can be alternatively named 2-ethyl-2-(N-ethyl-n-butylamino)2,6-acetoxylidide, having the structural formula /C H: C H3 4) i C'HaCHzOHflJH; C H3 0 H2 0 H8 2-dimethylamino-2', 6'- c aproylxylidide, which can be alternatively named 2-n-butyI-Z-dimethylamino-Z,6' acetoxylidide, having the structural formula ternatively named 2-n-propyl-2-pyrrolidino-2',6'-acetoxylidide, having the structual formula i CHr-C H The compounds of the invention can be prepared in accordance with the following partial class reactions:

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 given in the representative examples hereinafter.

The racemic compounds may be resolved into their dand l-optical isomers by treatment with land d-tartaric acid.

The compounds of the invention are useful as local anaesthetics in the conventional manner and employing conventional dosages thereof. These bases may be conventionally used in the form of solutions of their pharmaceutically acceptable salts, e.g., the hydrochlorides, tartrates and citrates.

The invention will be further illustrated by the following examples:

EXAMPLE 1 This example illustrates the preparation of Z-diethylamino-2', -n-butyroxylidide or or. (diethylamino) nbutyro-2,6-xylidide.

(u-Bromo n butyryl chloride).-Redistilled thionyl chloride (2.40 moles) was added to a-bromo-n-butyric acid (1.20 moles) in a 1000 ml. flask attached to a reflux condenser and drying tube. The mixture was heated to refiux for 5 hours. Excess thionyl chloride was distilled off with the bath temperature up to 120 C. The reaction mixture was kept at 2530 C. for one hour at water pump vacuum, whereafter the bath temperature was raised slowly to 80 C., at which point the a-bromo-mbutyryl chloride started distilling; B.P. 48-50" C.; yield: 1.10 moles (92%). A product sufiiciently 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 u-bromo-n-butyryl chloride at 80100 C. for 1.5-2 hours after the main bulk of thionyl chloride had been distilled 01f.

(oz Bromo-n-butyryl-2,6-xylidide) .a-Bromo-n-butyryl chloride (1.005 moles) was added to a cold mixture (5-10 C.) of 2,6-xylidine (0.92 mole) and glacial acetic acid (814 ml.) in a four liter bottle, quickly mixed, and quickly followed by a cold solution of sodium acetate trihydrate (315.6 g.) in water (1610 ml.). The bottle was closed and shaken for 30 minutes. The precipitate was filtered and washed several times by slurrying in water to remove the acetic acid as etficently as possible. It was then dried in air or in vacuum; M.P. 198200 C.; 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.

[m (Diethylamino)-n-butyro-2,6-xylidide] .--a-BI'OI110- n butyryl 2,6 Xylidide (0.0148 mole), diethylamine (0.0444 mole), and anhydrous benzene (25 ml.) were heated at 100 C. for hours in a pressure vessel. After cooling, the diethylammonium bromide was filtered off and the benzene solution extracted with three 25 ml. portions of 1 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 u-(diethylamino)-n-butyro- 2,6-xylidide (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- 226 C. (decomp.). Calculated for C H ClN Or C, 64.3; H, 9.11; N, 9.37. Found: C, 64.4; H, 9.12; N, 9.39. I.R. (KBr disc, hydrochloride) 1 3175 (s, NH amide), 2980 and 2938 (shoulder) (s, CH and CH 2577 (s, NH+), 2490 (s, NH+), 1685 (s, amide I), 1599 (w, Ph), 1530 (s, amide II), 1479 (s), 1232 (s, amide III), 787 (5, Ph 3 adjacent hydrogens out of plane) cm.- N.M.R. (CDCl base), 6 1.10 (t, 9H, CH -CE3), 1.602.10 (m, 2H, CHCH CH 2.18 (s, 6H, Ph CH 2.68 (q, 4H, NC CH 3.25 (t, 1H, COCH), 6.98 (s, 3H, Ph), 8.73 (s broad, 1H, NHCO). A gas chromatographic analysis of the compound showed the presence of one single peak.

EXAMPLE 2 This example illustrates the preparation of Z-(N-ethyln-propylamino) 2',6' butyroxylidide or a-(N-ethyl-n propylamino)-n-butyro-2,6-xylidide.

(a-Bromo-n-butyryl 2,6 xylidide).This compound was prepared as described in Example 1.

(a-Iodo-n-butyryl-2,6xylidide) .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 (1200 ml.) were mixed in a 3000 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 one 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 odide ion. The precipitate was then dried in air and/or in a desiccator. Yield: 243 g., M.P. 220-222 C. (decomp.).

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

The uncrystallized product contains some of the bromo compound but was sufliciently pure for the following step.

[a-(n-Propylamino)-nbutyro 2,6-xylidide].-Method (a): n-Propylamine (67.9 g., 1.15 moles) and a-iOdO-D- butyryl-2,6-xylidide (121.5 g., 0.383 mole) were mixed w th anhydrous benzene (1220 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 LR.) was discarded. The filtrate and washings were co)mb1ned and evaporated leaving a yellow residue (143.4 g.

The residue was treated with 380 ml. 1 M hydrochloric acid. An insoluble solid was filtered off and washed with ether. The acid filtrate was extracted with ether and an additional precipitated solid was filtered 011 and combined Wll'h the primarily obtained insoluble solid. The weight of the combined solid fractions was 156.2 g. (I). The acid filtrate (II) 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 I and the acid solution II were corn-t bined 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 evaporated yielding 93 g. of a partly solidifying marooncolored residue.

This residue was dissolved in 80 ml. of ether in a separatory funnel and equilibrated with 200 ml. phosphate 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 bulfer solution 6.3 g. of an oil could be obtained on raising the pH to 11 and extracting with ether. This fraction contained mainly the fl-substituted isomer, and was discarded.

Method (b): u-Bromo-n-butyryl 2,6 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 HCl (200 ml.). The suspension was washed with two 100 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: 51.0 millimoles (81%). The hydrochloride hydrate was prepared from the base with ethereal hydrogen chloride and addition of water. Recrystallized from ethanol/ether it melted at 199-1995 C. 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-xylidide (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 90 C. After cooling, water (110 ml.) was added with stirring for fifteen minutes followed by 4 M HCl (110 ml.). The solution was washed with ether (3x 100 ml.) and made alkaline with 7 M NaOH to pH 10-11. The freed base was taken up in ether (3 100 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. 203-203.5 C.; yield: 0.126 mole (52%). Calculated for C H ClN O: C, 65.3; H, 9.34; Cl, 11.3. Found: C, 65.2; H, 9.29; Cl, 11.3. LR. (KBr disc, hydrochloride) 11 3175 (s, amide NH), 2970 and 2940 (s, CH and CH 2580 (s, NH+), 2505 (s, NH 1680 (s, amide I), 1595 (w, Ph), 1531 (s, amide II), 1474 (s), 1227 (s, amide III), 778 (s, Ph 3 adjacent hydrogens out of plane) cmr N.M.R. (CDCl base) 6 1.06 (t, CH CH 1.26 (t, CH Cg [9H for the two triplets], 1.58-2.48 (m, 4H, cg cm), 2.53 (s, 6H, PhCHs), 2.82-3.30 (m, 4H, NCH2 a 3.72 (t, 1H, COCH), 7.98 (s, 3H, Ph). A gas chromatrographic analysis showed one single peak.

EXAMPLE 3 The racemic compound of Example 2 was resolved into the dand l-optical isomers by the following procedure:

The racemate of a-(N-ethyl-n-proplamino)-n-butyro- 2,6-xylidide base (9.73 g., 0.3519 mole) was dissolved in a mixture of l-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 4 C. 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 (I) were recrystallized repeatedly from water until constant optical rotation was obtained [a] =8.3. The mother liquid was made alkaline with 7 M 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 d-t-artaric acid (1.73 g., 0.0115 mole) in 6.4 ml. water with heating. From the cold solution (4 C.) crystals (II) were obtained which were recrystallized repeatedly from water until constant rotation was obtained,

The bases were liberated from the two tartrates with sodium hydroxide in water. The bases from (I) and (II) 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, 184- 185 C.

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

EXAMPLE 4 This example illustrates the preparation of Z-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 12 C. and 2-bromo-n-valeryl chloride (0.349 mole) was added rap idly. After quick mixing a precooled (5 C.) solution of sodium acetate trihydrate g.) in water (340 ml.) was immediately added and the mixture was shaken for circa 30 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 189-1905 C. After recrystallization from ethanol the melting point of the colorless crystals was 190-190.5 C. Yield: 65-78%. Calculated for C H BrNO: C, 54.9; H, 6.38; Br, 28.1. Found: C, 54.9; H, 6.33; Br, 28.2.

2-diethylamino-Z,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 C. for 35 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 4 N hydrochloric acid (3 X 50 ml.), the acid extract washed with ether (3X 50 ml.), and based out with 7 N sodium hydroxide under cooling and stirring and in the presence of ether (100 ml.). After two further extractions with ether (2X 50 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. ethanolzether (3:5) twice M.P. 205-206 C. Calculated for clqHggclNzo: 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. I.R. (KBr disc, hydrochloride): 3170 (mw, NH amide); 2968 and 2930 (m, CH and CH 2560 (m, NH+); 1677 (s, amide I); 1593 (w, Ph); 1528 (s, amide II); 1472 and 1433 (ms); 1230 (mw, amide IH); 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), pyrrolidine (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 ml.). The acid solution was washed with ether (2X 50 ml.) whereafter it was made alkaline with 7 N sodium hydroxide and extracted with ether (3 X 50 ml.). The ether extract was dried (Na SO and the solvent evaporated in vacuo. The hydrocloride 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 238-240 C. Calculated for C H N OC1: C, 64.7; H, 8.49; CI, 11.9. Found: C, 64.9; H, 8.59; Cl, 12.1. LR. (KBr disc, hydrochloride): 3450 (in, 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 II); 1469 (ms); 1227 (m, amide III); 781 (ms, 3 adjacent pH hydrogens out of plane).

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

2-n-butylamino 2,6 butyroxylidide.-A mixture of 2-iodo-2', butyroxylidide (0.0315 mole), n-butylamine (0.0945 mole) and anhydrous benzene (100 ml.) was refluxed for hrs. After cooling, the benzene and excess n-butylamine were evaporated in vacuum. The residue was taken up in 1 N hydrochloric acid, washed with ether (3X 25 ml.)., filtered, made alkaline to a pH of 9 with 7 N sodium hydroxide and extracted with ether (4X 25 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. 92-95 'C. Calculated for C H ClN O-H O: H O, 5.71. Found: 5.73 (Karl Fischer). A sample was dried at high vacuum and elevated temperature. Calculated for C H ClN O: C, 64.3; H, 9.11; CI, 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 90 C. for 5 hrs. After cooling, the clear amber-colored solution was mixed with 10 ml. of water, stirred for 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 11 with 7 N sodium hydroxide and the separating base taken up in ether (4X 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 202.5-204.5 C. Calculated for C I-I ClN O: C, 66.1; H, 9.56; Cl, 10.8. Found: C, 66.1; H, 9.71; Cl, 11.1. LR. (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 II); 1470 (s); 1228 (m, amide III); 781 (m, 3 adjacent Ph hydrogens out of plane).

EXAMPLE 7 This example illustrates the preparation of Z-dimethylamino-2',6'-caproylxylidide.

2-bromo 2',6 caproylxylidide.-A mixture of 2,6- xylidine (0.125 mole) and glacial acetic acid (115 ml.) was cooled to 10 C. 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 (50 C.) 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 methanolzwater (approx. 15:1) twice; M.P. 167-169 C. Yield: 67%. This material was sufiiciently pure for the subsequent reaction. The pure compound (one further recrystallization) had a M.P. of 168.5-169 C. Calculated for C H BrNO: C, 56.4; H, 6.76; Br, 26.8. Found: C, 56.2; H, 6.40; Br, 25.9.

2-dimethylamino 2,6' caproylxylidide.-A mixture of 2-bromo-2,6-caproylxylidide (0.119 mole), dimethylamine (0.356 mole) and benzene (177 ml.) were heated in a pressure vessel for 22 hrs. at 100 C. 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 (1 X 50+2 25 ml.), the acid solution based out to pH 11 with 7 N sodium hydroxide and extracted with ether (3X 50 ml.). The combined ether extracts were dried (Na SO and evaporated in vacuo. From the residue the hydrochloride was prepared with ethereal hydrogen chloride. It was recrystallized from abs. alcoholzether (1:8) twice, yielding colorless crystals (0.0992 mole) melting at 193.5- 194.5 C. Calculated for CmHgqClNgOZ 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. I.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 II); 1470 (s); 1236 (mw, amide III); 776 (m, 3 adjacent Ph hydrogens out of plane EXAMPLE 8 This example illustrates the preparation of 2-pyrrolidino-2',6'-n-valeroxylidide.

2-iodo-2',6-n-valeroxylidide.A mixture of 2-bromo- 2',6-n-valeroxylidide (0.137 mole), potassium iodide (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 1965-1975" C.; yield 0.105 mole of a product sufiiciently pure for the next synthetic step. Another recrystallization brought the M.P. to 197- 198 C. Calculated for C H INO: C, 47.1; H, 5.48; I, 38.3. Found: C, 47.3; H, 5.36; I, 38.2.

2-pyrrolidino-2,6'-n-valeroxylidide.-A mixture of 2- iodo 2,6' n valeroxylidide (0.0754 mole), pyrrolidine (0.226 mole) and benzene (65 ml.) was heated in a pres sure vessel for 24 hrs. at C. After cooling, the benzene and excess pyrrolidine were evaporated in vacua. 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. (126-1275 C.); yield 4.9 g. From the mother liquors 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. I.R. (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).

In the tables presented below the following code designations have been used:

A is Z-diethylamino-2',6'-n-butyroxylidide.

B is 2-(N-ethyl-n-propylamino)-2',6'-n-butyroxylidide. C is the d-optical isomer of the racemic compound B.

D is the l-optical isomer of the racemic compound B.

E is 2-diethylamino-2,6'-n-valeroxylidide.

F is 2-pyrrolidino-2',6'-n-butyroxylidide.

i CHIC/HZ 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 while Tables VII and VIII contain comparative data on the acute toxicity of several of these local anaesthetic compounds. i

TABLE V.PERIDURAL ANAEST'HESIA IN THE DOG 1 Duration of block of support of weight in minutes Percent concentrate base E X Y Mature male beagles are surgically prepared by implantation of a cannula into a lumbar vertebra so that drug solutions (5 ml.) may be administered into the peridural space. Aiter administration of local anaesthetic solutions, the animals are examined at intervals for duraation of motor block (support of weight).

Nora-A11 solutions contained 1:100,000 epinephrine;

TABLE VI.IRRITATION STUDIES: RABBIT INTRADE RMAL WHEALS 1 Percent Irritation index concentrate as base A B X Y Z 'lest method given in Truant, A.P.: Arch. Int. Pharmacodyn. 115: 483-497 (1958), which is incorporated by reference herein.

NOTE.-SO1i1i;i0l1S did not contain epinephrine.

TABLE I.--RAT SCIATIC NERVE BLOCKS 1 Duration in minutes =i= standard deviation Percent concentrate as base A B C D E F G H X Y Z 279116 114:1:23 160=i=27 140i12 135:};18 236:5538 126=e13 212=e34 1235:10 l18:i:15

313 97516 191=|=57 179:1:27 1785:18 3d mile 213 16239 126=i=21 172:1:31 2s7=|=se zeszhae 1 180;};43 2803:42 185=i=28 146=l=l8 1 Test method given in Truant, A.P.: Arch. Int. Pharmacodyn. 2 Some animals blocked 12 hrs.

115: 483497 (1958), which is incorporated by reference herein. solutions contained 1:100000 epinephrine.

TABLE II.GUINEA PIG INTRADERMAL WHEALS TABLE VIL-ACUTE TOXICITY IN FEMALE MICE Percent Duration in minutes=i=standard deviation LD o and 95% Fieller confidence concentrate limits: rug/kg. as base as base A B X Y Z Compound Intraperitoneal Intravenous 0.125 15e=i=11 955:8 154:1:15 182:i=4 7a=|=9 96d=l2 54(461l7) 9.4(8. 2-11) 110=i=4 1745:12 252=i=5 110413 1013:12 62(5382) 5.8(5. 1-6. 5) 169%:8 232=l=11 3i410 i17=i=6 117:1:14 15.9(14. 0-18. 6)

l2li12 1665:19 .4-6. Test method given in Bulbring, E. and Wajda, I.: J. Pharmacol. 9) Exp. Therap. 85: 78-84 (1945), which is incorporated by reference herein. 11. 3(9. 2-13. 9) Nora-All solutions contained 1:1000,000 epinephrine. 6. 4(5. 5-7. 3) 25 (22-33;

Noam-Solutions did not contain epinephrine.

TABLE III.-PERIDURAL ANAESTHESIA IN THE CAT TABLE TOXICITY IN MALE Duration of block of support of weight in minutesistandard deviation LDio and 95% Fielggiiggigfidence limits. mg.kg. Percent concentrate ase A B X Y sex A B X Male 136(102-172 71(53-90) 1.0.- 1:135:24 308z|=2l 2 296=i=77 2D 2365:26 88 5:10 Female 94(73-120) 124(98-160; 7 3) 1 Test method given in Duce, B. R., Zelechowski, K., Camougis, contained 1:200'000 epinephrine 1G. and Stniiitl, E.fR.: Brit. J' Anaesth. 41: 579-587 (1969), which is 1100 ore e re 8191106 erein.

IExie efiect s observed at this concentration. Irritation indices reported in Table VI are determined Norm-All solutions contained 12100,!)00 epinephrine. the followmg 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 TABLE IV-PERIDURAL ggi IN THE GUINEA of edema, and presence or absence" of necrotic tissue in the wheel. The grading is done on an arbitrary numerical Duration of block of support of weight in W u minutes 5: standard deviation scale, and a mean irritation ndex is calculated for Percent concentrate all wheels at a given concentration. base E G X Y The test method employed for the acute toxicity studies 39M 465:8 38=l=7 10 reported in Tables VII and VIII was as follows: 2%; 5? 351 iii; 79 Sexually mature male or female animals are used. 1 as m I v B 29 H 6 Animals are divided into groups of 10 and dosed with 1 Testmethod given nTan an now et. cs. 48 19 8 r whichismcorpomed by reference harem I f drug solution or vehicle. After being dosed, animals are 2 Three animals died 5 minutes post-injection and one animal did not observed at intervals for several hours for overt effects and fatalities. Survivors are housed as groups according Norn.-Al1 solutions contained 1:100,000 epinephrine.

to dose level and checked once daily for the duration of 1 1 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 Logit Chi Square Method of Berkson, I. Am. Stat. Assoc, 481565 (1953).

The comparative data presented in Tables I-VIII above establish that-the racemic compounds of the invention generally are appreciably longer lasting local anaesthetics, particularly at use concentrations of 1% or 2%, than are the comparative homologous compounds Y and Z and yet they have a satisfactory low level of tissue irritation and a satisfactory low acute toxicity.

What is claimed is:

'1. A 2-alkyl-2-alkylamino-2',6'-acetoxylidide local .anaesthetic compound having the structural formula wherein R is ethyl, propyl or butyl; R and R are each separately seelcted 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; and the pharmaceutically acceptable salts thereof.

2. The local anaesthetic compound defined by claim 1 which is Z-diethylamino-Z,6'-n-butyroxylidide.

3. The local anaesthetic compound defined by claim 1 which is 2-(N-ethyl-n-propylamino)-2,6'-n-butyroxylidide. t

4. The local anaesthetic compound defined by claim 1 which is 2-diethylamino-2,6'-n-valeroxylidide.

5. The local anaesthetic compound defined by claim 1 which is 2-pyrrolidin0-2',6-n-butyroxylidide.

6. The local anaesthetic compound defined by claim 1 which is 2-(N-ethyl-n-butylamino)-2',6'-n-butyroxylidide.

7. The local anaesthetic compound defined by claim 1 which is Z-dimethylamino-Z',6-caproylxylidide.

8. The local anaesthetic compound defined by claim 1 which is Z-pyrrolidino-Z',6'-n-valeroxylidide.

9. The d-optical isomers of the compounds described in claim 1.

10. The l-optical isomers of the compounds described in claim 1.

References Cited UNITED STATES PATENTS 3,544,587 12 /1970 Brown 260326.3

3,542,850 11/1970 Jansen et a1. 260471 2,904,586 9/1959 Ruschig et al. 260--500 OTHER REFERENCES Lofgren et al.: Svensk. Kem. T id., vol. 58 (1946), 206- 217. t t

Schonenberger et al.: Archiv der Pharmazie, 301 Bd JOSEPH A. NARCAVAGE, Primary Examiner US. Cl. X.R.