NO135934B - - Google Patents

Description

The present invention relates to

preparation of 2-alkyl-2-alkylamino-2',6'-acetoxylidide compounds with local anesthetic activity.

Two acylxylidide local anesthetics are commercially available, namely N-n-butylpipecolyl-2,6-xylidide or bupivacaine pre-

look under the trademark "Marcaine" with the structural formula:

and diethylaminoaceto-2,6-xylidide or CO-diethylamino-2,6-dimethylacetanilide or lidocaire which is marketed under the trade name "Xylocaine" and has the structural formula

However, while bupivacaine or "Marcaine" is a long-acting local anesthetic, the drug has the disadvantage of irritating tissue, and while lidocaine or "Xylocaine" does not irritate tissue, it has the disadvantage of not being a long-acting local anesthetic.

Other commercially available local anesthetics include ct-propylaminopropiono-2-toluidide or prilocaine sold under the trade name "Citanest", α-pyrrolidinoaceto-2,6-xylidide or pyrocaine sold under the trade names "Endocaine" and "Dynacaine", and N-methylpipecolyl-2,6-xylidide or mepivacaine sold under the trade name "Carbocaine". However, these local anesthetics have a short-term effect.

It is therefore a main purpose of the invention to provide substances which generally have the combined properties of long-lasting local anesthetic effect or high local anesthetic activity, a satisfactory low level of tissue irritation, as well as an acceptable low acute toxicity.

..The compounds produced according to the invention, are 2-alkyl-2-alkylamino-2', 6'-acetoxylidide compounds with local anesthetic action, with formula: in optically active or racemic form, as well as pharmaceutically acceptable salts thereof, where R<1> means ethyl, propyl or butyl, R<2> and R^ ..individually mean methyl, ethyl, propyl or butyl, or Ro together with R^ can also mean tetramethylene, the total number being

12 ^

carbon atoms in R , R and R ^ are at least six. The compounds are thus racemic substances and therefore local anesthetics as d- or 1- optical isomers fall within the framework of formula I.

Representative compounds include, among others: 2-diethylamino-2',6'-n-butyroxylidide which can alternatively be termed 2-ethyl-2-diethylamino-2',6'-acetoxylidide, with the structural formula: 2-(N-ethyl-n-propylamino)-2',6'-n-butyroxylidide which may optionally be called 2-ethyl-2(N-ethyl-n-propylamino)-2',6'-acetoxylidide, with the structural formula : 2-diethylamino-2',6'-n-valeroxylidide which can optionally be designated 2-n-propyl-2-diethylamino-2',6'-acetoxylidide with the structural formula 2-pyrrolidino-2',6f<->n-butyroxylidide which can also be called 2-ethyl-2-pyrrolidino-2',6'-acetoxylidide, with the structural formula 2-(N-ethyl-n-butylamino)-2',6'-n-butyroxylidide, which can also be called 2-ethyl-2-(N-ethyl-n-butyl-amino)-2',6'- acetoxylidide, with the structural formula 2-dimethylamino-2',6'-caproylxylidide which can alternatively be called 2-n-butyl-2-dimethylamino-2',6'-acetoxylidide, with the structural formula and 2-pyrrolidino-2',6'-n-valeroxylidide which can also be called 2-n-propyl-2-pyrrolidino-2',6'-acetoxylidide, with the structural formula

The compounds of formula I are prepared according to the invention as illustrated in the last step in reaction core A below

and at the last two steps in reaction scheme B.

12 "5 where R , R and R have the meaning as above and X denotes a bromine or chlorine atom. The bromine atom in the compound of formula: can also be transferred to iodide before the substance is used in step 2 above.

The iodine atom in the penultimate step above can be replaced with a bromine atom.

where R 1 , R 2 , RJ ? and X has meaning as above. Instead of KJ

can you use other halogenating agents such as Na J.

As alkylating agents, you can for example use (CgH^^SO^ or <C>2<H>5<J>•

The racemic substances can be separated into their d- and 1-optical isomers by treatment with 1- and d-tartaric acid.

The compounds prepared according to the invention are useful as local anesthetics in a known manner in usual doses. The basic compounds can be used in a known manner in the form of solutions of their pharmaceutically usable salts, for example as hydrochlorides, tartrates or citrates.

Parenteral solutions can be given epidurally, subarachnoidally and by infiltration. Solutions, gels, ointments and spray preparations prepared from the bases or their pharmaceutically acceptable salts can be applied topically to mucous membranes or damaged skin, for example exfoliated skin.

The compounds can be used in concentrations of 0.25 - 2% and in doses of 75 - 3^0 mg. However, the concentrations and doses that are braked must not be restricted to these areas, but must be determined individually, taking into account factors such as the patient's age and body weight, the clinical indication and the route of administration.

In the following, the invention will be further illustrated by examples:

Example 1.

_ This example illustrates the preparation of 2-diethylamino-2', 6'-n-butyroxylidide or α-(diethylamino)-n-butyro-2,6-xylidide.

(q-bromo-n-butyryl chloride)- Redistilled thionyl chloride (2.40 mol) was added to α-bromo-n-butyric acid (1.20 mol) in a one liter flask fitted with a reflux condenser and drying tube. The mixture was refluxed for 5 hours. Excess thionyl chloride was distilled off under a bath temperature of up to 120°C. The reaction mixture was kept at 25-30°C for one hour under water pump vacuum, after which the bath temperature was slowly increased to 80°C and at this point the α-bromo-n-butyryl chloride began to distill off, boiling point 48-50°C, yield: 1.10 moles ($92). A product sufficiently pure for the reaction below was prepared by omitting the vacuum distillation and leaving a current off

dry argon (or nitrogen) bubble through the α-bromo-n-butyryl chloride' at 80 - 100°C for 1.5 - 2 hours after the bulk of the thionyl chloride had distilled off.

(q-bromo-m-butyryl-2, 6-xylidine)-α-bromo-n-butyryl chloride (1.005 mol) was added to a cold mixture (5-10°C) of 2,6-xylidine ( 0.92 moles)

and glacial acetic acid (814 ml) in a four liter flask, quickly mixed and quickly added a cold solution of sodium acetate trihydrate (315»6 g) in water (1610 ml.). The flask was closed and shaken for 30 minutes. The precipitate was filtered off and washed several times by slurrying in water to remove the acetic acid as effectively as possible. The substance was then dried in air or in vacuum, melting point 198-200°C, yield: 0.74 mol (80%). Calculated for G^H^BrNO: C 53.3, H 5.97, Br 29.6, found: c 53-3, H 5-79, Br 29.7.

(α-(diethylamino)-n-butyro-2,6-xylidide)-α-bromo-n-butyryl-2-,6-xylidide (O.OI48 mol), diethylamine (O.O444 mol), and anhydrous benzene (25 ml.) was heated at 100°C for 15 hours in a pressure vessel. After cooling, diethylammonium bromide was filtered off and the benzene solution was extracted with three 25 ml. portions of 1 M hydrochloric acid. The acid extract was washed with 25 ml. ether and adjusted 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 in vacuo, after which α-(diethylamino)-n-butyro-2,6-xylidide (0.00499 mol = 33.7%) was obtained as a waxy solid. The substance was converted into the hydrochloride salt with ethereal hydrochloric acid and the salt was recrystallized three times from a mixture of absolute ethanol and ether, mp 224.5-226°C (decomp.) - Calculated for C-^H^CII^O: C 64.3, H 9.11, N 9.37. Found: C 64.4,

H 9.12, N 9.39. I.R. (KBr disk, hydrochloride), 3175 (s, NH amide), 2980 and 2938 (shoulder) (s, CH^ and CH2), 2577 (s, NH+), 249° (s,NH+), I685 (s, amide I), 1599 (w, Ph), I53O (s, amide II), 1479 (s), - 1232 (s, amide III), 787 (s, Ph, 3 neighbor hydrogen out of plane) cm"<1 >. N.M.R. (CDCl^, base), «1.10_(t, 9H, CH2 -CH^), \ J>0 - 2.10 (m, 2H, CHCH^H^), 2.18 (s, 6H, Ph -CH ^), 2.68 (q, 4H, N-CH^CH^) , 3.25

(t, 1H, COCH), 6.98 (s, 3H, Ph), 8.73 (s broad, 1H, NHC0). A gas chromatographic analysis of the compound showed only a single peak.

Example 2

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

IfH - bromo-n-butyryl-2, 6-xylidide) This compound was prepared as described in example 1.

( op. iodo-n- butyry 1- 2 , 6- xylidide) - dj-bromo-n-butyryl-2 , 6-xylidide (224.7 g> O.832 mol), powdered potassium iodide (I9I.2 g = 1.15 mol) and anhydrous methanol (1200 ml) were mixed in a 3 liter flask fitted with a reflux condenser, mechanical stirring and heating jacket. After refluxing for 3 hours, the mixture was cooled for 30 minutes with continued stirring, transferred while stirring to a beaker containing 2.5 liters of distilled water and left for 1 hour. The precipitate was filtered off and pressed as dry as possible. The precipitate was then filled back into the beaker and carefully stirred with approx. 1.5 liters of distilled water and filtered again. The procedure was repeated until the filtrate was free of bromine and iodine ions. The precipitate was dried in air and/or in a desiccator. Yield: 243 g, melting point 220-222°C (decomp.).

The prepared preparation was almost colourless. Recrystallization from 95% ethanol gave a product m.p. 223.5°^ during decomposition.

The uncrystallized product contains some bromine compound, but was sufficiently pure for the following step.

(of-(n-propylamino)-n-butyro-2,6-xylidide)

Method a n-propylamine (67.9 g = 1*15 mol) and of-iodo-n-butyryl-2,6-xylidide (121-5 g = 0.383 mol) were mixed with anhydrous benzene (1220 ml.) in a flask fitted with a reflux condenser, mechanical stirrer and heating jacket and boiled at reflux for 8 hours. The light yellow solution was filtered from a yellow precipitate which was washed carefully

■with ether. The precipitate (no C=0 band in the I.R. spectrum) was discarded. The filtrate and washing solution were combined and evaporated

a yellow residue (143-4 g)•

The residue was treated with 380 ml of 1 M hydrochloric acid. An insoluble solid was filtered off and washed with ether. The acidic filtrate was extracted with ether and a further precipitate was filtered off and combined with the previously obtained insoluble solid. The total weight of the solid precipitates was 156.2 g (I). The acidic filtrate (II) was washed with a further 4 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 of residue and was discarded. The solid fraction I and the acidic solution II were combined and treated with 7 M NaOH and the base liberated thereby extracted with ether. After drying over anhydrous sodium sulfate, the ether extract was filtered and evaporated to give 93 g of a partially solidified brown-red residue.

This residue was dissolved in 80 ml of ether in a separatory funnel and adjusted to equilibrium with 200 ml of phosphate buffer at a pH of 7.3. Keeping the pH at 7-3, the buffer solution was extracted three more times with 80 portions of ether.

The ether extracts gave 79.2 g of a base containing essentially the desired compound and sufficiently pure for the next step.

From the buffer solution, 6.3 g of an oil could be obtained by raising the pH to 11 and extracting with ether. This fraction contained mainly the (3-substituted isomer) and was discarded.

Method b q( -bromo-n-butyryl-2,6-xylidide (63.1 mmol), n-propylamine (254 mmol), sodium iodide (63.1 mmol), and absolute ethanol (180 mL) were refluxed for 6, 5 h. The alcohol was evaporated in vacuo and the residue mixed with 0.5 M HCl (200 mL). The suspension was washed with two 100 mL portions of ether, 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 mmol (8l%). The hydrochloride hydrate was recovered from the base with ethereal hydrochloric acid and addition of water. Recrystallized from ethanol/ether, the substance melted at 199 -199.5° C. Calculated for the base (<C>15H24N20) : C 72.5' H N 11>3- Found: C 72.5» H 9-81,

N 11.2.

( Of-( N- ethyl- n- propylamino)- n- butyro- 2, 6-xylidide)

of-(n-propylamino)-n-butyro-2,6-xylidide (0.243 mol) and freshly distilled diethyl sulfate (1.0 mol) were mixed in a flask fitted with a 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 15 minutes followed by 4 M HCl (110 mL). The solution was washed with ether (3 x 100 mL) and basified with 7 M NaOH to pH 10-11. The liberated base was taken up in ether (3 x 100 ml), the extracts

was 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/isopropyl ether, melting point 203-203.5°C, yield: 0.126 mol (52%). Calculated for C-^H^CIN^: C 65.3, H 9-34,

Cl II.3. Found: C 65.2, H 9.29, Cl 11.3. I.R. (KBr disk hydrochloride))J 3175 (s, amide NH), 2970 and 2940 (s, CH^ and CHg), 2580

(s, NH<+>), 2505 (s, NH<+>), 1680 (s, amide I), 1595 (w, Ph), 1531

Cs, amide II), 1474 (s), 1227 (s, amide III), 778 (s, Ph, 3 neighboring hydrogens out of plane) cm"<1.> N.M.R. (CDCl^, base)£ I.06 (t,CH2CH^), 1.26 (t, CH2CH„) (9H for the two triplets), I-58 - 2.48 (m, 4H, CH2CH3), 2.53 (s, 6H, PhCH^), 2.82 - 3.3O ( m, 4H, NCH 2 ), 3.72

(t, 1H, COCH), 7.98 (s, 3H, Ph). Gas chromatographic analysis showed a single peak.

Example

The racemic compound from Example 2 was resolved into

d- and -^-optical isomers as follows:

The racemate of -(N-ethyl-n-propylamino)-n-butyro-2,6-xylidide base (9.73 <g>> °-3519 mo1) was dissolved in a mixture of ^-tartaric acid (5- 28 g, O.3519 mol) and 19«5 ml of water by gentle heating. After filtration, the solution was cooled and stored at 4°C. The crystals that formed were filtered from cold. The mother liquor was concentrated to approximately half the volume and a further precipitate was obtained. The combined solids (I) were recrystallized several times from water until constant optical rotation was obtained, (o() D^5= -8.3°. The mother liquor was made alkaline with 7 M sodium hydroxide and extracted with ether. The ether was evaporated and 3.18 g (O.OII5 mol) of residual base was recovered, and the compound dissolved in a solution of ^-tartaric acid (1.73 S» 0.0115 mol) in 6.4 nil of water under heating. From the cold solution (4°C) crystals (II ) which was recrystallized repeatedly from water to constant rotation,

(a) D = +8.6°. The base was liberated from the two tartrates with sodium hydroxide in water. The bases from (I) and (II) had specific rotations of +34»1° °g -32«8°, respectively. The rotation for their hydrochlorides was +6.2° and -6.2°, respectively, after recrystallization from absolute ethanol - ether. Their melting points were identical, 184-185°C.

The racemic substances from examples 1 and 4-8 can be separated into their d- and 1- optical isomers by a method corresponding to that described in example 3"

Example 4»

The example shows the preparation of 2-diethylamino-2',6'-n-valeroxylidide.

2-bromo-2', 6', n, valeroxylidide - 2,6-xylidine (0.347 mol) and glacial acetic acid (310 ml) were mixed in a 2 liter flask. The mixture was cooled to 12°C and 2-bromo-n-valeryl chloride (0.349 mol) added rapidly. After rapid mixing, a pre-cooled solution (5°C) of sodium acetate trihydrate (85 g) in water (340 ml) was immediately added, and the mixture was shaken for approx. 30 minutes. The solid was filtered off and washed carefully and repeatedly with water until the filtrate was free of bromide ions. After drying in a desiccator over a potassium hydroxide flake, the solid (0.345 mol) melted at 18g-190.5oC. After recrystallization from 95% 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-2T,6'-n-valeroxylidide - A mixture of 2-bromo-2',6'-n-valeroxylidide (0.176 mol), diethylamine (0.528 mol), and benzene (125 mD was placed in a pressure vessel and heated to 100°C for 35 hours. After cooling, the dark brown contents were filtered and the solid (23.2 g diethylammonium bromide) washed thoroughly with benzene. The filtrate was extracted with 4 N hydrochloric acid (3x50 ml), the acid extract washed with ether (3x50 mL), and basified with 7H sodium hydroxide with cooling and stirring and in the presence of ether (100 mL). After t<q >further extractions with ether (2x50 mL), the combined

ether extracts dried (Na 2 SO 4 ) and the ether evaporated giving a residue weighing 16.5 g. The hydrochloride was prepared from the residue by dissolution in ether and addition of ethereal hydrochloric acid. The hydrochloride was recrystallized from absolute ethanol:ether (3:5) twice, mp 205-206°C. Calculated for C-^H^ClNgO: C 65.3,

H 9.34, N 8.95. Found: C 65.2, H 9.49, N 9.15. Only a distinct peak was obtained by gas chromatography of the salt. i.r. (KBr disk, the hydrochloride): 317O (mw, NH amide), 2968 and 293O (m, CH^ and CH2), 256O (m, NH<+>), 1677 (s, amide I), I593 (w, Ph , 1528 (s, amide II), 1472 and 1433 (ms), 1230 (mw, amide-III), 775 (m, 3 neighboring Ph-hydro genes out of plan).

Example 5»

This example shows the preparation of 2-pyrrolidino-2', 6'-n-butyroxylidide.

2- pyrrolidiono- 2', 6'- n- butyroxylidide - A mixture of 2-bromo-2',6'-butyroxylidide (0.0463 mol), pyrrolidine (0.13 g mol) and benzene

(100 ml) was refluxed for 21 hrs. Solvent and excess pyrrolidine were evaporated in vacuo leaving a partially solid residue which was dissolved in 1 N hydrochloric acid (125 mL). The acid solution was washed with ether (2x50 mL), then made alkaline with 7 N sodium hydroxide and extracted with ether (3x50 mL). The ether extract was dried (Na 2 SO 4 ) and the solvent was evaporated in vacuo. The hydrochloride was prepared by dissolving the residue in ether and adding a sufficient quantity of gaseous hydrochloric acid, yield 0.0414 moles. After two recrystallizations from 95% ethanol:ethyl acetate (1:1) the colorless crystals melted at 238-240°C. Calculated for C^H^^OCl: C 64.7, H 8.49, Cl 11.9. Found: C 64.9, H 8.59, Cl 12.1. I.r (KBr discs, hydrochloride): 3450 (m, broad), 3175 (ms, amide NH), 2965 and 2927 (ms, CHo and CH2), 2670, 263O, and 2600 (ms), 2475 (mw, NH< +>), l680 (s, amide I), 1529 (w, Ph), 1525 (s, amide II), I469 (ms), 1227 U, amide III), 781 (ms, 3 neighboring ^Ph hydrogen atoms out of plan).

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 mol), n-butylamine (0.0945 m°D °S anhydrous benzene (100 ml) was refluxed for 5 hours. After cooling, the benzene and excess n-butylamine were evaporated in vacuo. The residue was taken up in 1N hydrochloric acid, washed with ether (3*25 mL), filtered, made alkaline to pH 9 with 7 U sodium hydroxide, and extracted with ether (4x25 mL). The ether extract was dried (Na 2 SO 4 ) and the ether evaporated in vacuo to a colorless oil (0.0153 mol).

(This oil is sufficiently pure for the ethylation step described below). A hydrochloride was prepared from the oil base in anhydrous ether by adding ethereal hydrochloric acid solution. The product formed could only be crystallized with difficulty from a variety of solvents. When dissolved in water, crystals formed on standing. The hydrochloride hydrate formed was recrystallized from aqueous ethyl acetate, melting point 92>95°C' Calculated for C-j^H^Cl^O . H 2 O: H 2 O 5.7 I. Found: 5.73 (Karl Fischer) A sample was dried in a high vacuum at an elevated temperature. Calculated for Cl6H27ClN20: C 64.3, H 9.11, Cl 11.9. Found: C 64.1, H 9.26,

Clause 11.8.

2-( N- ethyl- n- butylamino)- 2*, 6*- n- butyroxylidide - A mixture of 2-n-butylamino-2',6'-butyroxylidide (the oily crude base (O.OI53 mol) mentioned above) and diethyl sulfate (O.O996 mol)

was heated at ^ 0°C for 5 hours. After cooling, the clear amber solution was mixed with 10 ml of water, stirred for 15 minutes and mixed with 10 ml of 4 N hydrochloric acid. The acid solution was washed with ether and the phases were separated completely, the upper ether layer being discarded each time. The pH was adjusted to 11 with 7 N sodium hydroxide and the separated base taken up in ether (4 x 30 mL). After drying (Na2S0^), the ether was evaporated and a residue was obtained which constituted the crude base (0.0395 mol). The hydrochloride was prepared by dissolving the residue in anhydrous ether and introducing ethereal hydrochloric acid. Recrystallization from abs. alcohol: Ether, gave colorless crystals, m.p. 202.5-204.5°C. Calculated for C-^H^CIN^: C 66.1, H 9.56,

Clause 10.8. Found: C 66.1, H 9.71, Cl 11.1. I.R. (KBr disk, hydrochloride) : 316O (ms, amide NH), 296O (s) and 2890 (msMCH^ and CHg), 2615-2595 (m, broad), 2505 (m, NH<+>), 1680 (s , amide I), 1594

(w, Ph), 1530 (s, amide II), 147° (s), 1228 (m, amide III), 781

(m, 3 neighboring Ph hydrogen atoms 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 mol) and glacial acetic acid (115 ml) was cooled to 10°C in a 1 liter flask and 2-bromocaproyl bromide (O.I36 mol) added and mixed rapidly. As quickly as possible this was followed by a cold solution (50°C) of sodium acetate trihydrate (45 g) in water (190 ml). The mixture was shaken for 45 minutes and filtered. The precipitate was washed thoroughly and repeatedly with water until it was free of bromide ions. It was then dried in a desiccator over potassium hydroxide flakes and recrystallized from methanol:water (ca. 15=D twice, melting point 167-169°C. Yield 67%. This substance was sufficiently pure for subsequent reaction. The pure compound (still a recrystallization) had

a melting point of l68.5-l69°C. Calculated for C-^H^BrNO: C 56.4,

H 6.76, W 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 mol), dimethylamine (0.356 mol) and benzene (177 ml) was heated in a pressure vessel for 22 hours at 100°C. After cooling, the reaction mixture was filtered. The weight of precipitated dimethylammonium bromide indicated that 97% of the bromine compound had reacted. The filtrate was extracted with 4 N hydrochloric acid (1x50+2x25 ml), the acid solution made alkaline to pH 11 with 7 N sodium hydroxide and extracted with ether (3x50 ml). The combined ether extracts were dried (Na 2 SO 4 ) and evaporated in vacuo. The hydrochloride was prepared from the residue with ethereal hydrochloric acid. This was recrystallized from abs. alcohol:ether (1:8) twice, giving colorless crystals (0.0992 mol) melting at 193.5-194.5°C. Calculated for <C>l6<H>27C1N20:C 64«3» H 9.10, N 9.37, <C>l II.9. Found: C 64.2, H 9.04, N 9.52, Cl 12.0. i.r. (KBr disk, hydrochloride):3l85 (m, amide NH), 2950 and 2920 (ms-m, CH^ and CH2), 245O (ms, NH+), 1682 (s, amide I), 1591 (w, Ph) , I53O (s, amide II), 1470 (s), 1236 (mw, amide III), 776 (m, 3 neighboring Ph hydrogen atoms out of plane).

Example 8.

This example illustrates the preparation of 2-pyrrolidino-

2',6'-n-valeroxylidide.

2-. iodo- 2' ^'- n- valeroxylidide - A mixture of 2-bromo-2',6'-n-valeroxylidide (0.137 mol), potassium iodide (0.274 mol) and dry methanol (375 ml) was refluxed with stirring for 3 hours. After cooling, 1 liter of water was added to the yellow-coloured reaction mixture and this was allowed to stand with stirring for 15 minutes. The precipitate was filtered off, washed repeatedly with water until the filtrate was free of halide ions and dried. After recrystallization from 95% ethanol, the substance melted at 196.5-<1>97.5°C, yield .0.105 mol, and the product was sufficiently pure for the next synthesis step. A new crystallization brought the melting point up to 197-198°C. Calculated for C-3H-lqJNO: C 47.1, H 5.48, J 38.3. Found: C 47-3, H 5.36,

J 38.2.

2-pyrrolidino-2',6'-n-valeroxylidide - A mixture of 2-iodo-2',6'-n-valeroxylidide (0.0754 mol), pyrrolidine (0.226 mol) and benzene (65 mL) was heated in a pressure vessel for 24 hours at 100°C. After cooling, the benzene and excess pyrrolidine were evaporated in vacuo. The residue was stirred with water (150 ml) for 30 minutes and filtered. 7 N sodium hydroxide (to pH 11) was added to the filtrate with stirring and after 30 minutes the solid base was filtered off, washed thoroughly and repeatedly with water and dried in a vacuum. The crude base (14 g) was recrystallized from aqueous ethanol to a constant melting point (126-127.5°C), yield 4*9 g« From the mother liquor a further 2.7 g was obtained. Total yield: 37%. Calculated for C-^<HggNgO:> 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 CHg), 1645

(s, amide I), 1593 (w, Ph), 1529 (s, amide II), 1478 and I465 (ms), 770 (s, 3 neighboring Ph hydrogen atoms out of plane).

Example 9»

This example illustrates pharmaceutical preparations. The solution containing 0. <2>5. 0* 50. 0. 75 and 1. 0% 2-( N- ethylpropylamino)- 2', 6'- butyroxylidide

hydrochloride without added vasoconstrictor. pH 3.5- 4.5.

The active ingredient in the above solution can be replaced with 2-diethylamino-2',6'-n-valeroxylidide hydrochloride.

Example 10.

The example illustrates pharmaceutical preparations. Solutions containing 0.25, 0.50, 0.75 and 1.0 f° 2,-(N-ethyl-propylamino)-2',6'- butyroxylidide hydrochloride with epinephrine 1:200,000. pH 3.5 - 4. 5

Tables I to V contain comparative data showing the time of action or duration for a number of these local anesthetic compounds, table VI contains comparative data regarding the tissue irritation for a number of the local anesthetic compounds, tables VII and VIII contain comparative data regarding the acute toxicity of several of the above local anesthetics, while Tables IX to XI contain data from human clinical trials with compound B.

Irritation indications listed in Table VI are measured

in the following way:

Swellings or filipenses are induced on the shaved backs of albino rabbits by intradermal injection of aqueous solutions of the compounds. 24 hours later, each swelling is assessed: Presence and degree of erythema, presence and degree of edema and presence or absence of neurotic tissue in the swelling. Grading is done according to a random numerical scale and an average "irritation index" is found for all swellings at a given concentration.

The test method used for determining acute toxicity listed in tables VII and VIII is as follows: Sexually mature male or female animals are used. The animals are divided into groups of 10 and given a dose of active solution or carrier medium. After each dose, the animals are observed at certain intervals to find obvious effects and possible deaths. Surviving animals are placed in groups by dosage level and examined once daily during the study period to detect any delayed deaths.

One calculates LD^q and 95 $ Fieller probability limits (or 95% approximation limits) according to the least squares method (Minimum Logit Chi Square Method) Berkson J.Am.Stat.Assoc. 48:565

(<1>953). Surgical operations have been carried out on patients who have received compound B either epidurally (Table IX), intracostally (Table X), or in the brachial plexus region (Table XI). In particular, the surprisingly short application times, the satisfactory depth and duration of anesthesia and the complete absence of systemic and local side effects must be emphasized. An unexpected beneficial effect of the muscle relaxation could be observed, which facilitated the surgical interventions, e.g. during abdominal operations.

The comparative data listed in Tables I-VIII show that the racemic compounds' produced according to the invention usually have a considerably longer duration of action, especially at concentrations of 1% or 2%, than the compared homologous compounds Y and Z, and at the same time they have satisfactorily low tissue irritation and satisfactorily low acute toxicity.

Claims (2)

1. Analogous methods for the production of local anesthetic active compounds with the formula: in optically active or racemic form, as well as pharmaceutically acceptable salts thereof, where R 1 means ethyl, propyl or butyl, R 2 and R^~* > each means methyl, ethyl, propyl or butyl, or R? together with R^ can also mean tetramethylene, the total number being 1 2 ^ carbon atoms in R , R and R J are at least six, grade i-sertvedat A) a compound with the formula: where R<1> has the above meaning and Y is a bromine or iodine atom, is reacted with a compound of the formula: 2 "5 where R and R have the meanings given above, for the formation of • a compound of formula I, or B) a compound of the formula: where R1 and Y have the meanings given above, are reacted with a compound of the formula:. where R 2 has the meaning given above, for the formation of a compound with the formula: after which this compound is reacted with an alkylating agent to form a compound of formula I, and after which the thus formed compound of formula I is, if desired, dissolved in its optical antipodes and/or reacted with a pharmaceutically acceptable acid. 2. Analogy method according to claim 1, for the preparation of a compound with the formula: or a pharmaceutically acceptable salt thereof, characterized a) a compound with the formula: where Y is a bromine or iodine atom, is reacted with a compound of the formula: for the formation of a compound of formula IA, or b) a compound of the formula: where Y has the meaning given above, is reacted with a compound of the formula: for the formation of a compound of the formula: after which this compound is reacted with an alkylating agent to form a compound of formula IA, and after which the thus formed compound of formula IA is, if desired, dissolved in its optical antipodes and/or reacted with a pharmaceutically acceptable acid.