Патент USA US2410791код для вставки
Patented Nov. 5, 1946 r 2,410,791 UNITED 7STATES PATENT ’ OFFICE -' Karl G. Pleger, Rochester, N. Y., and Arthur J. Hill, New Haven, Conn ., assignors to American Cyanamid Company, New York, N. Y., ‘a core poration of Maine No Drawing. ' Application March 31, 1942, - Serial No. 436,959 , 5 Claims. (crate-+475) . 1 , This case relates to the 'alkamine esters of sym I metrical diaryl-succinic acids. - the usefulness of its estersas an anti-spasmodic _ and as a mydriatic. Many different compounds have been synthe The present invention is particularly concerned sized in the course of a long. search for a local with alkamine esters of symmetrical diaryl-sub anesthetic which would be a satisfactory sub stitute for‘ cocaine. Although cocaine is the 6 stituted succinic acids which may be represented . by the following formula: standard against which, local anesthetics are ' usually compared, it has many undesirable prop erties. Notable among these are its high tox "icity and narcotic character, because of which 10 its clinical use has practically disappeared. De spite the large amount of work which has been ' carried out inattempts to find a suitable sub stitute, the list of effective and non-toxic com in which ’Ar represents an aryl radical and E ingly small, not more than about half a dozen having gained any wide acceptance. There still phenyl, tolyl, aminotolyl, anisyl, naphthyl, eth represents an alkamine radical. Ar may be ‘a pounds suitable for clinical use remains sur'pris- \ 15 substituted or unsubstituted aryl radical such as remains a real demand for a compound ‘which is highly active as a local anesthetic and which is at the same time free from irritating, toxic and narcotic properties. > oxynaphthyl and the like. E preferably represents an alkamine radical of the type formula: ' - R: -niN< Most of the satisfactory local anesthetics are alkamine esters of various acids although the _ RI particular properties of any alkamine ester de-. in which R1 represents a hydrocarbon residue such pend upon the particular aminoalcohol and par 25 as that of an alkyl radical and Re and Rh repre ticular acid from which it is made. For ‘exam sent the same or different radicals or R2 and .Rs ple, in the past it has been, believed that the alka may represent hydrocarbon residues ‘which with mine esters derived from acids containing an , the N go to make up a heterocyclic ring such as aromatic group were most effective as local an that of'piperidine or morpholine. Typical exam esthetics, followed in descending order of activity 30 ples of the aminoal‘cohols of the type concerned - by alkamine ‘esters of acids containing groups in'the present application are: p-diethylamino such as pyrrol, thiophene, furan and alkyl. Ac ethanol, 'y-diethylaminopropanol, p~dipropylami cordingly, for example, the hydrochloride 'of the _ noethanol, .p-dibutylaminoethanol, t-dipropylam p-diethylaminoethyl ester of p-aminobenzoic acid 43-N,N-ethylcyclohexylaminoethanol, has been widely used although it is not particu 35 inobutanol, 6~dibutylaminobutanol, p-N,N-phenylethylami larly satisfactory as a surface anesthetic nor of particularly satisfactory duration as a nerve block. noethanol, 4-diethylaminocyclohexanol, p-4-mor-1 pholinoethanol, 3-5-dimethyl - p - 4-morpho1ino It has been found, however, that’ the’. - ethanol, p-piperidinoethanol and the like. _ properties can be varied almost at will by proper Typical of the acids, with the alkamine esters substitution in the acid _from which the ester is 40 of which the present invention is particularly derived. Not only do these various substitutions concerned is diphenyl-succinic acid. In the fol a?ect the general properties but speci?cally a?ect lowing disous'sion‘ and examples thisacid will be - the usefulness of the alkamine esters for various used to illustrate the invention. However,‘ it is purposes. Varying the substituents of the acid intended to be merely illustrative and not to limit a?ects'the relative anesthetic activity of esters 45 the inventionv to this particular acid. derived from it with a designated aminoalcohol, Symmetrical 'diphenyl-succinio acid may be both as a surface anesthetic and as a nerve block. readily prepared in the form of its vethyl ester Varying the _substituents oi’ the'acid also affects by treating the ethyl ester of phenyl acetic acid 2,410,791 4 Exam“: 1 in an ether, solution with iodine and sodium ethoxide. The action is readily carried out and Ethyl-sym-diphenyl succinate the ester occurs as both the mesovand racemic forms. Separation of the two may be easily made by means of their different solubilities. Either form upon saponi?cation in alcoholic caustic so lution of sodium or potassium hydroxide gives a mixture of meso and racemic diphenyl-suc cinic acid. If desired the two acid forms may OCHCOOClH! Olnooocna, Dry pulverized sodium ethylate fr om 11.4 parts of sodium was suspended in 140 parts of dry ether be separated by the, difference in the solubility in a one liter three neck ?ask supplied with con of their alkaline earth metal salts. Since any attempt to form an acid chloride in denser, stirrer and dropping funnel. To this sus pension was added 70 parts of phenyl acetic ester treatment of the acid _ the usual manner, as byproduces anhydrization ‘ with thionyl chloride, of the dipheriyl-succinic acid, some form of alco 15 holysis is necessary as a means of forming the and then over a period of one hour, during stir ring and cooling, a solution of 54.6 parts of iodine in 280 parts of dry ether. The reaction mixture became turbid from formation of an insoluble alkamine esters. If an alcoholysis is carried out, white precipitate. The mixture was ?nally stirred the products are all in the same form whether for two hours at room temperature. Water and the mesa or the racemic form is used as a start sodium thiosulphate were then added. The white ing material. ~ Since the alkamine esters are the 20 precipitate, now suspended in the water layer was products which aredesired there is, therefore, ?ltered off and crystallized from 95% alcohol. little practical advantage in separating either the A pure white crystalline solid melting at mil-141° two forms of ester or thetwo forms of the acid. C. was obtained. This is the ,B- or meso ester. Direct esteri?cation is highly impractical be The ether layer of the ?ltrate was then separated, cause of the low reaction rates and poor yields. dried over sodium sulfate, the ether distilled off Our preferred procedure is to form a simple alkyl ~ and the residue recrystallized from alcohol. The ester and then to carry- out a catalyzed ester resulting product was washed with ether which interchange, preferably removing the replaced dissolved the a- or racemic ester leaving. the meso alcohol as fast as it is liberated. according to the processset forth in the Hill and Holmes appli 30Y, ester. To recover the racemic ester, the ether was evaporated from the ?ltrate and the residue re cation Serial No. 431,822, filed February 21, 1942.. crystallized from petroleum ether. The ester thus Eor this process the mixture of meso and racemic obtained melted at 80-82° C. - ethyl esters of diphenyl-succinic acid produced EXAMPLE 2 as set forth above is an excellent starting ma 35 Di-(p-diethylaminoethyl) -sym-diphenyl terial. The alkamine ester bases are usually clear, succinate somewhat amber colored oils which distill at fair ly high temperatures even under reduced pres sure. They are usually soluble in alcohol, acetone and ether and usually insoluble in water. These 40 alkamine esters are slightly basic in reaction and may be readily converted into salts such as To a solution of 0.2 part of sodium in 32- parts the hydrochloride, nitrate, sulfate, hydrobromide, Oonoooomcnmonsm Olmooo omcmNwium of p-diethylaminoethanol was added 26 parts of _ meso-diphenyl-succinic ester. The mixture was phosphate, tartrate, citrate andthe like. The hydrochlorides are probably the easiest to pre then heated by means ‘of an oil bath at Mil-150° C. for 44 hours. After completion of the reac tion, the excess p-diethylaminoethanol was dis The hydrochlorides, for example, are generally white crystalline solids having a sharp melting 50 tilled off and the residue shaken with a mixture of dilute hydrochloric acid and ether until solu point and being in general very soluble in water, pare and are usually preferable because of this fact. , ‘ . tion was complete. The hydrochloric acid layer was separated, washed twice with fresh portions of ether and then treated with potassium car alcohol, acetone, chloroform and benzene. The hydrochloric acid salts of the base in aqueous solution exhibit high activity and low toxicity as bonate until a sludge formed. The sludge was ' . ' If so desired the quaternary compounds such 55 then extracted with ether until removal of the aminoester was complete. The ether solution of as the methiodide,‘ ethobromide and the like may surface anesthetics. » be readily prepared. The quaternary compounds the base was dried over sodium sulfate, the solu tion ?ltered, the ether distilled off and the residue vacuum distilled. After-a few drops of foreruns .60 an amber colored liquid distilled at 220-235° C. hydrochlorides of high melting point which are - likely to;be extremely hygroscopic, The quater (5 mm.) . nary compounds may be readily prepared by EXAMPLE 3 have a certain advantage in that they are usually more readily crystallized than are some of the . treating the base in an alcoholic solution with a compound such as'methyl or ethyl bromide and the salts may be precipitatedby removing, a. por tion of the alcohol and adding ether to the resi - - succinate due until precipitation stops. The quaternary compounds have sharp melting points when puri ?ed by recrystallization from a suitable solvent such as an acetone-ether mixture. ‘ Di- (p-diethyl‘aminoethyl) -sym-driphenyl - ‘- Ooncooomonmconm, 70 The present invention will be more fully illus trated in connection with the following examples ~ olnoooomommcimh The procedure of Example 2 was followed in an experiment using the racemic dlphenyl-succinic which are illustrative and not by way- of limita ester. In this case, the amber colored product tion. All parts are by weight unless otherwise 75 boiled at 225-230” 0. (5 mm.). noted. ' . ~ ‘ 2,410,701- ' The properties of the two aminoesters prepared Exams: '7 by the above methods, as well as the properties of their hydrochlorides were identical. Therefore Dt-(v-diethyldminopropyl) -sym-diphen11l Y‘ succi-i ' the two esters have the same form. nate 5 Exzmru 4 @cncooomomoamwmm Hydrochloride of di-(p-diethylaminoethyl) -sym diphenyl succinate ' Olnccoomomommomm . @cncooomommotmhnm 10 I C>l11ooocmo1zmwmmnei ,_In an experiment using the ‘procedure‘of Ex ample 6 racemic-diphenyl-succinic ester was al coholized by means of a solution of sodium in 'Y-diethylaminopropyl alcohol.‘ ‘In this case the A portion of the aminoester obtained by the‘ temperature was kept at 1,45-l55° C. for 44 hours. alcoholysis of meso-diphenyl-succinic ester with Subsequent treatment of the reaction product ?-diethylaminoethanol was dissolved in dry ether 15 was thesame as in the preceding experiment. ~ and treated with dry hydrogen chloride until no The reddish brown product boiled at 235-255° C. more precipitate formed. The ether was then de (5 mm.). ‘ . canted and the gummy precipitate shaken with another portion of dry ether which was in turn 20 decanted. Dry acetone was added to the hydro ,Hydrochloride ' sym-diphenyl of di - (‘Y - diethylammopropyl) succinate ' chloride. Part of the hydrochloride dissolved, and part assumed the form of a ?occulent precipitate. After standing in a refrigerator overnight, the pre cipitate was ?ltered off, washed with acetone and dry ether and then dried ina vacuum desiccator overnight. The hydrochloride was a- white, friable, _ non-hygroscopic amorphous Glucooomomommoiuotnol. _ powder A portion of ‘the aminoester obtained by the \ which melted at 188-190‘ C. The salt was soluble in water and alcohol but insoluble in acetone and ether. alcoholysis of meso-diphenyl-suc'cinic ester with . 'v-diethylaminopropanol was dissolved in dry . ether and treated with dry hydrogen chloride - EXAMPLE 5 until precipitation was complete. - The ether was then decanted and the gummy precipitate shaken with another portion of dry‘ether which was also Hydrochloride of di-(s-diethyzammoethyz) -sym diphenz/l saccinate 35 decanted. ' Dry acetone was added to the hydro chloride. After it had been shaken, the salt as sumed the form of a ?occulent precipitate but would not dissolve to any considerable extent. A small amount of ether was added to the mixture A portion of the aminoester obtained by the alcoholysis of ‘racemic-diphenybsuccinic ester _with p-diethylaminoethanol was subjected to the treatment of Example 4. The same observations were noted. The product was identical with the hydrochloride obtained in the previous experi ment; melting point, 189-190° C. 40 which was then allowed to stand in a refrigerator overnight.’ The solid was ?ltered off, washed . with acetone and ether and dried in a vacuum ‘ desiccator. ,The hydrochloride was white, dry ‘and friable and melted at 165-170° C. Although ; soluble in water and alcohol, the salt was insolu ble in'acetone and ether. EXAMPLE 9 ‘ EXAMPLE Hydrochloride of di - (‘Y - diethyldminopropyl) - ni-(v-diethylam-inopromll) -sym-dii>henyl succi- _ 50 , nate To a solution of 0.2 part of sodium in 25 parts - - @0110 0 o onlonlommcinornoi @cncobomomommomm _ Ollie 0o CH:CH:CH2N(C:H5): sym-‘diphenyl saccinate 5,5 Gino OOCHrOH2CHzN(G;Hs)2.HCl A portion of the aminoester obtained by‘the alcoholy'sis of racemic - diphen'yl - succinic ester >with 'v-diethylaminopropanol was subjected to of 'y-diethylaminopropanol was added 12 parts of meso-diphenyl-succinic ester. The mixture .60 the treatment of Example 8. The same observa tions were noted. The ?nal product had the was heated by means of an oil bath at 140-155” C. same appearance, melting point and solubilities for 55 hours. The excess 'Y_diethylaminopro as the hydrochloride obtained in Example 8. panol was then distilled off under reduced pres sure and the residue shaken with a. mixture of dilute hydrochloric acid and ether until solution was effected. _ The hydrochloric acid layer was separated, washed twice with fresh portions of ether and then treated with potassium carbonate until a sludge formed. ' The sludge was then ex tracted four times with ether to remove the free aminoester. ‘The ether solution of the base was dried over sodium sulfate, ?ltered, the ether dis- * tilled off and the residue vacuum distilled. After a few drops of foreruns a reddish brown liquid distilled at 230-250° C‘. (5v mm.). . EXAMPLE 10 _ 65 .Di-(p-di-n-butylaminoethyl) -sym-diphenyl suc cinate ' @0110 oocnzommcrum @Jmc o ocmcmmcinoz Y To a solution of 0.1 part or sodium in 14 parts of p-di-n-butylaminoethanol was added 9 parts 75 of meso-diphenyl-succinic ester. The mixture 2,410,791 n moved and the residue distilled. At 255-215‘ 0. 'was heated at 180° C. for 44 hours. and at 160°C. (4 mm.) the aminoester distilled as an amber ' for 24- hours. The excess p-dibutylaminoethanol ' was then dlstilled'o? under reduced pressure and color oil. _ ‘ Hydrochloride of diw-di-n-butylaminopmpull sym-diphem/Z succinate two layers were extracted twice with ether to re move any diphenyl-succinic ester. - Emu: 13 the residue shaken with a mixture of dilute hy drochloric acid and ether. An oily third layer formed between the acid and ether layers. The The‘ two lay- . ers were then combined and treated with potas slum carbonate until a sludge formed. The tree 10 aminoester was separated from the sludge by means of several ether extractions. The "ether extracts were dried over sodium sulfate, the solu-. A portion of the di-(v-di-n-but laminopropyl) tion ?ltered, the ether distilled oil and the resi- . diphenyl suceinate was dissolved i dry ether and due vacuum distilled. After a few drops of fore 15 treated with dry hydrogen chloride until precipi runs,v the aminoester distilled over at 230-250° C. tation was complete. The ether was decanted, (5 mm.) as a brownish oil. the hydrochloride vigorously shaken with another , EXAMPLE l1 Hydrochloride of di-(p-di-n-butylaiminoethgl) sym-diphenyl succmate portion of dry etherto remove any adherent hydrogen chloride and this other in turn poured 20 o?. Dry acetone caused part of the oil to solidify and dissolved the remainder. After- standing in a refrigerator overnight, the mixture was ?ltered, Owmoooomdmmcmhncx Ooncooomonmwaimncl the solid washed with acetone and ether and then dried in a vacuum desiccator overnight. The ?nal 25 product was a white amorphous powder which melted ‘at ,171-‘1'73° C. The hydrochloride dis solved in alcohol and hot acetone but gave a- . A portion of the di-(p-di-n-butylaminoethyl) - somewhat turbid water solution. sym-diphenyl succinate was dissolved in dry Several of the alkamine esters, notably the di ether and treated with dry hydrogen chloride (p-diethylaminoethyl) diphenyl sucoinate, the di until precipitation was complete. After the re action mixture had been shaken the ether was decanted from the oil, fresh dry ether added, the mixture again shaken and then allowed to stand in a refrigerator overnight. The‘ ether was de (q-diethylaminopropyl) diphenyl succinate, and the di- ('y-dibutylaminopropyl) diphenyl succinate in the form of their hydrochloride salts in aqueous solution are particularly useful as local anesthet ics. The di- ('y-diethylaminopropyl) canted‘ and the oily hydrochloride treated with dry acetone. After it had been shaken for a few diphenyl succinate, for example, as a surface anesthetic is but slightly less active than cocaine, produces moments a considerable portion of the hydro anesthesia for three times the duration of cocaine chloride solidi?ed while the remainder dissolved. and is only about 115 as toxic. Similarly as a nerve The solid was ?ltered oil, washed with dry ace 40 block, it is only approximately 1/3 as toxic and has tone and ether and, dried in a, vacuum desiccator. a~ duration of about four times that of cocaine. It The resulting hydrochloride was a white, friable, . has the further advantage that when mixed with amorphous powder which melted at 158-160° C. ' epinephrine and injected subcutaneously it does It was fairly soluble in water and alcohol but in not produce a discoloration. soluble in acetone and ether. We claim: 1. Di-(p-diethylaminoethyl) diphenylsuccinate. 2'. Di - (7 - diethylaminopropyl) diphenylsucci Di- (v-di-n-butylamin0pr0mll) -sym-diphenyl . succinate ' - ' nate. > @0110 ooomomommoaim 3. Di - iql-dibutylaminopropyl) 50 ~ Olncooomomcnmmmn nate. diphenylsucci- ' ' ' 4. As new compositions of matter, the di-esters v of symetrical dlphenyl succinic acid having the To a solution of 0.2 part of sodium in 26 parts of 'y-di-n-butylaminopropanol was added 10 parts of meso-diphenyl-succinicester. ‘The mixture‘ it Hi N/R was heated by means of'an oil bath at 180-200“ C. for 48 hours. After the excess 'y-dibutylaminor propanol had been removed under reduced pres 60 sure, the residue was shaken with a mixture of wherein R’ represents a divalent aliphatic radical containing 2 to 4 carbon atoms and R represents ‘mained clear showing that the aminoester had an alkyl group containing 2 to 4 carbon atoms. dissolved in the acid. _ The acid layer was sepa 65 v5. As new compositions of matter, the water rated and treated with potas'siumcarbonate until soluble addition salts of the di-(dialkylamino a. sludge formed. The free base was separated alkyl, symmetrical diphenyl succinates of claim 4. ether and hydrochloric acid. The acid layer be-. came brown in color while the ether layer- re from the sludge by means of several ether ex- ‘ tractions. The ether extracts were dried over sodium sulfate, the solution ?ltered, the ether KARL G. PLEGER. ARTHUR J. HILL.