US2954373A - Cinnamate esters - Google Patents

Description

all.

CINNAMATE ESTERS Seymour L. Shapiro, Hastings on Hudson, Louis Freedman, Bronxville, and Harold Soloway, Tuckahoe, N.Y., ass gnors to US. Vitamin .& Pharmaceutical Corporation, a corporation of Delaware No Drawing. Filed Apr. 8, 1258, Ser. hi0. 127,036

. '6 Claims. '(Cl. 260-439.)

This invention relates to cinnamate esters of aminoalcohols. These esters are particularly useful as anesthetics and the invention will be illustrated by description'in connection with such use. i r p The esters of this present invention are cinnama te esters of fi-dialkylarnino-a-phenylethanols and may he represented by the formula 1 wherein R and R are lower alkyl groups or are joined as the carbon content of such groups being not less' that 1 4 carbon atoms and not more than 6 carbon atoms, and R is selected from the group consisting of hydrogen chlorine. The esters maybe used in the formulas shown for as salts thereof with non-toxic acids.

Within these narrow structural limits, relatively nontoxic compounds yielding pronounced anesthetic 'efic'cts are obtained. Furthermore, under cor'ice'nt'ratiorls' pro- Patented Se t. 27, 1950 ice " WghiohI-yis .thegquantity of compound' per r1111; "0f solution requiredtoefiiect 159% anesthesia as established irQm'th plot pigeoncentration percent anesthesia.

:FIiheutoXidity .ef the individual -compeunds Wvas al o established {by administration subcutaneously (so) to .mice, in terms 0f themiuimum dose required to be lethal to mice and expressed :as LDm-m, in milligrams of compon-ndzperE-kilogram of mouse.

The therapeutic index was then calculated "by dividing the LD by the ED the result being ,a single -figure embracing the anesthetic effectiveness of the compound and its inherent toxicity.

The results are shown in Table I. It will be noted that the compounds shou/ therapeutic indices of 400- 1670, as compared to the index of 13 found for procaine,

' the standard local anesthetic, in comparative tests.

heterocyclic amino radicals with the attached nitrogen,

*ducing effective anesthesia, a desirable lack of irritancy is noted upon injection. i y 7 1 s As "compared to the standard procaine, We obtain marked improvement in the therapeutic "index' for ou'r new anesthetics. Thus, We have raised thether apeuti'c index of 13, found for procaine in our test methodfto as high as 400 and even up to 1670 forour compounds 4 under comparable conditions. One feature of our compounds, therefore, is their low or non-toxicity coupled with unusually effective anesthetic action. Individually, the compounds exhibit toxicities as low as one fifth that of procaine. Coupled with this safety factor of decreased toxicity is the high potency as anesthetics which, in *indi vidual cases, is 2530 times that of procaine. This desirable combination of normally opposed properties will be more clearly reflected in the pharmacological studies reported in Tablesi and II. I e

When employed as a local anesthetic, any suitable method of application known in'the'art mafbeu'sed. These compounds, furthermore, may be'adniinisteredf'ni a surgical lubricant jelly base.

EVALUATION AS ANESTHEIIQS I The compounds of this invention were evaluated by the method of Chance and Lobstein, J. Pharmacol., 82, 203 (1944), for deter-mining the median eifective dose of a local anesthetic ,When applied to the cornea of a guinea pig eye. v

A known concentration of solution of the local anesthetic is applied to both eyes of a guinea pig and the eyes keptlaathed with this solution for 2 minutes. The eyes are then blotted to remove excess solution. 7

Table I.-Anesthati't: potency in guinea pig cornea and to z'cicity'ofcompounds of the formula CONTROLS-COMPOUNDS NOT A PART OF INVENTION is, ""e'm" .f '7 I jotia 5-4 500 93 6. Procaine 1 15.0 200 '13 7'- xylpeeiue 6.8 .225 v as v important .feature of therapeutic utilityis freedom from 'irritancy'upon 'injectionr'Using solutions of equivalent or superior anesthetic potency as compared to the control drugsprocaine'and Xylocaine, the irritancy was established by the irritancy rating in percent, and rcsultslrave been expressed in Table II.

Table II Conceiitra Irritancy' Compound No. tion, Rating,

mg./ml Percent in Table III.

The irritancy test was done in the following manner: Prcedure.--Four rats used for each compound tested Backs of rats are shaved very closely. Intradermal injectionof test compound (0.20 cc.) is administeredto each of-4 rats. I p

Observati0ns.Site of injections is observed at 3 intervals-2 4 hours, 48 hours and 72 hours, post-injection. The degree of irritancy is recorded as follows:

0 No irritant effect. Visible redness. Visible redness, induration. f++ -More extensive redness, induration. Maximum lesion, with necrosis.

In determining the irritancy rating, 'each'plus is scored as l; :L as 0.5. After 3 observations, the total number of plusses divided by the maximum possible plusses 36)=irritancy rating. Thus, a non-irritant compound has a low irritancy rating while the more irritant the compound, the higher the irritancy rating.

These data clearly reflect the superiority of our compounds as anesthetic agents over the control drugs commonly used clinically. In addition, the importance of the proper selection of /R1 7 v N is apparent for high anesthetic potency.

METHOD OF MANUFACTURE The required amino alcohol intermediates for preparing the basic esters of this invention are prepared according to methods described in the literature (Emerson, I. Am. Chem. Soc., 67, 5 16 (1945)).

Table IIl.-Intermediate aminoalcohols of the type formula The esters described in this invention are prepared by the usual techniques from the appropriate intermediates. Suitably, we use cinnamoyl chloride with an equivalent proportion or a slight excess of the tertiary aminoethyl, either in the absence of solvent or in the presence of an inert organic solvent such as benzene, toluene, ether or acetonitrile. The tertiary aminoethanol selected is one containingR R and R that are to appear in the finished product. After a suitable reaction period, either at room temperature or at elevated temperatures controlled by the reflux temperature of the solvent, the reaction mixture is separated into products. In most instances,

the desired ester of aminoethanol, being basic, appears 7 as the" hydrochloride.

In general, the desired secondary amine, represented 73:;

by R R NH, is condensed with an oxide such as styrene oxide, p-chlorosty-rene oxide, and the like, such oxides containing the R desired in the final product, as indicated in the reaction below.

mercially available, are prepared by reaction of a (i rignard reagent, containing the R group desired in the finished product, with chloro-acetaldehyde (Chem. Abstn, 44, 1446i 1950 This gives the halohydrins. These I This salt is readily isolated and purified by recrystallization. Alternatively, if the hydrochloride is not readily crystallizable, it is dissolved-in water, alkalinized to liberate the free 'base of the ester, and the free ester then extracted into an organic solvent such as ether, benzene or chloroform, the organic solvent layer evaporated to dryness, and the product purified after such removal of the solvent by distillation under diminished pressure, the principal fraction being accepted.

Salts ofthe esters are readily prepared by the usual technique as, for example, by neutralizing our esters in turn, are dehydrohalogenated to yield the required oxides.

Typical of these steps is the reaction.

' Indicative of the class of amino alcohols prepared for use as intermediates in this invention by the general reaction described above, are the following compounds'listcd which are basic, by hydrochloric, hydrobromic, phosphoric, sulfuric, succinic, acetic, tartaric acid, or other non-toxic acid in a suitable solvent such as alcohol, water, etherv or benzene. The salts form directly. They are collected on a filter or recovered by evaporation.

Quaternary salts are prepared by reaction of the basic esters-with such quaternizing agents as methyl iodide, methyl sulfate, methyl toluenesulfonate, ethyl bromide,

V benzyl bromide, allyl bromide and ethyl bromoacetate. The required oxides, in the event that they are not com- The compounds of this invention, d1 mixtures, have optically active forms, and the individual optically active forms isolated by procedures familiar to those skilled in the art, are to be considered within the purview of this invention. 'The invention will be further illustrated by description in connection with the following specific examples showing the preparation of compounds of the invention. Unless specified to the contrary, references in these examples to removal of volatile solvent means removal by distillation, all temperatures are expressed as C., and the yields represent percentage of theory.

EXAMPLE 1.-2-( N-METHYL-Nd-PROPYLAMINO)-1- PHENYLETHYL CINNAMATE HYDROCHLORIDE I A solution of 6.7 g. (0.04 mole) of cinnamoyl chloride in '50 ml. of benzene was brought to reflux. To this was added 7.7 g. (0.04 mole) of Z-(N-methyl-N-i-propylamino)-l-phenylethanol in 50 ml. of benzene over a periodof 15 minutes with stirring and continued reflux. Heating and stirring were continued for 2 hours after addition was complete. On cooling, 10.8 g. (75%) of the hydrochloride of the product separated, melting-at 164-165 Recrystallization from methyl ethyl ketone yielded 8.4 g. (58%), melting at 164-166 (uncorn). Analysis.-Calcd. for C H ClNO C, 70.08; H, 7.28; N, 3.89. Found: C, 69.78; H, 7.10; N, 4.19.

EXAMPLE 2.2-HEXAMETHYLENEIMINO-1-PHENYL ETHYL 'CINNAMATE HYDROCHLORIDE This compound was prepared by the method used in Example 1, starting with 6.7 g. (0.04 mole) of cinnamoyl chloride, 8.8 g. (0.04 mole) of 2-hexamethyleneirnino-1- phenylethanol and 100 ml. of benzene. There was obtained 14.1 g. (91%) of crude hydrochloride, melting at 195-196", which was recrystallized from methanol to yield 10.3 g. (67%), melting at 208-210 (uncorr.).

Analysis.Calcd. for C H ClNO C, 71.58; H, 7.31; N, 3.63. Found: C, 72.07; H, 7.27; N, 3.93.

In a similar manner, 2-pyrrolidino-1-phenylethyl cinnamate hydrochloride and Z-piperidino-l-phenylethyl cinnamate hydrochloride are prepared from the appropriate reactants.

EXAMPLE '3.-2-DIETHYLAMINO-'1- (p-C'HLOROPHENYL) ETHYL CINNAMATE HYDROCHLORIDE The method of Example 1 was used to prepare this compound, starting with 3.3 g. (0.02 mole) of cinnamoyl chloride, 4.6 g. (0.02 mole) of Z-diethylamino-l-(p-chlorophenyl) ethanol and 100 ml. of benzene. Since the product did not precipitate directly, the solvent was removed at diminished pressure and the residue triturated with dry ether to yield, on filtration, 6.0 g. (76%) of solid which melted at 78-87". Recrystallization from isopropanol gave 4.1 g. (52%) of the hydrochloride of the product, melting at 93-96 (uncorr.).

Analysis.-Calcd. for C H ClNO C, 63,96; H, 6.39; N, 3.55. Found: C, 63.16; H, 6.89; N, 3.74.

EXAMPLE 4,-2-DIETHYLAMINO-1-PHENYLETHYL CINNAMATE The method of Example 1 was used to prepare this compound from 19.3 g. (0.1 mole) of Z-diethylamino-lphenyl ethanol, 16.6 g. (0.1 mole) of cinnamoyl chloride and 225 n11. of benzene. When no precipitation of hydrochloride could be observed, the solvent was distilled off at diminished pressure and the residue triturated with dry ether. Filtration of the resulting solid gave 31.3 g. (87%) of the hydrochloride of the product melting at 119-124". This was recrystallized from a mixture of isopropanol and isopropyl ether to yield 26.4 g. (74%), melting at 118-120 (uncorr.).

A portion of the hydrochloride was dissolved in 100 ml. of water, made basic with 40% aqueous sodium hydroxide and the liberated base taken up in 100 ml. of dry ether. The ethereal solution was dried over anhydrous magnesium sulfate and then filtered. Removal of solvent and distillation gave a 34% yield (overall) of the base, boiling at l76-178/0.28 mm.

Analysis.Calcd. for C H NO- C, 77.98; H, 7.79; N, 4.33. Found: C, 77.61; H, 7.59; N, 4.30.

Special compositions are made for the administration of the anesthetic in various manners.

For use in infiltration anesthesia, solutions are made to contain, for each ml, 1-50 mg. of the anesthetic agent in salt form, and sodium chloride 0.3-5.0 mg. with a preservative, examples being sodium bisulfate 0.1-2 mg,

benzoic acid 0.l-0.3 mg., or chlorobutanol 5 mg., and' the whole being diluted q.s. to 1 ml. with distilled water. Preparations are also made including in addition, 1 part of epinephrine to 20,00050,000 parts of the solution.

Other uses for these anesthetics include such applications as ophthalmic ointments and ointments for rectal disorders. These are prepared using formulations familiar to those skilled in the art.

It is to be understood that it is intended to cover all changes and modifications of the examples of the invention herein chosen for the purpose of illustration which do not constitute departures from the spirit and scope of the invention.

6 We claim: 1. A cinnamate ester selected from the group consisting of esters of the general formula 3. The compound of the formula H 0 i H 4. The compound of the formula 5. The compound of the formula 6. The compound of the formula References Cited in the file of this patent UNITED STATES PATENTS Cusic Feb. 17, 1953 OTHER REFERENCES Nazarov et al.: Chemical Abstracts, vol. 50 (1956), pp. 8634-35.

lzagirov et al.: Chemical Abstracts, vol. 50 (1956), p. 8

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION m Patent No 2 954 373 September 27 1960 Seymour L. Shapiro et al0 It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4 line 24 for "aminoethyl" read aminoethanol column 5 line 33 for "63 96" read 63.96

Signed and sealed this 4th day of April 1961a (SEAL) Attest: ERNEST W. SWIDER XXIX ARTHUR w. CROCKER Attestin Officer Acting Commissioner of Patents

Claims (2)

1. A CINNAMATE ESTER SELECTED FROM THE GROUP CONSISTING OF ESTERS OF THE GENERAL FORMULA

4. THE COMPOUND OF THE FORMULA