Патент USA US2404510код для вставки
Patented July 23,‘ 1946 _ 2,404,510 __ UNITED . STAT-ES » RATENT- OFF-ICE “ Loren M. Long, Detroit, Mich., assignor to Parke, 1 Davis & Company,-Detroit_, Mich., a ‘corporation ' J _ i’ _' ' of Michigan ' - ' Nobrawing. ' Application seetépi?ei as, 1344,“ l > Serial No. 555,759 8 Claims. -; (01. zoo-309.5)" a: ' ._ - -- ~ 2 The invention relates to'a new class'of chemical ' compounds which are valuable for therapeutic use, especially as anticonvulsants having rela ,. been‘. ‘madethey' are oxidized at‘ thefsulfidelink- _ age to the corresponding sulfones'.""‘:This"may be . The compounds of the, invention have-the gen eral formula, ‘ ' ' nAfter?the "sul?desubstituted}hydantoinsa‘have 1. tively high anticonvulsant activity combined with ,low toxicity. zerie e done by means of oxidizing agents known .to be ' e?ective in oxidizing sul?des to sulfones, suchas . hydrogen peroxide, chromic acid, peracetic acid and like oxidizing agents. 10 . .. . ’ The following examples serve to illustrate the invention: Preparation of p-isobutylmercaptoacetophe " none. I , CH3 where R is a straight, branched, or‘ cyclicE-alkyl 1-5 radical or an aryl or aralkyl radical such that the total number of carbon. atoms in R is not i more than 7. M of this formula represents‘ a member of the class hydrogen and basic elements or groups forming non-toxic salts of the hydan 20 toins, such as‘sodium, calcium, magnesium, am monium and substituted ammonium, for ‘exam ple, mono- and di-alkyl ammonium and, corre- ‘ sponding hydroxy alkyl ammonium. " ,- l The compounds of the invention can be used The method ‘of .Whitn'e'r and 'Reid (J.'A.- C158. orally'or by injection. For example, the average 43, 638 a (19211)‘) ';i's"us'eld'for the preparation‘ of adult person can start with, a dosage of 1/2 to 1 this‘ compound‘; :30"grams-'(0i75imole)‘ of sodium gram per day orally and increase the dosage slightly thereafter. hydroxide are dissolved in‘ 500 cc. of ‘70%ethano1; 1T0‘ the cooled solution are added 67.5 g." (0.75 The compounds are without odor when properly puri?ed. ' mole) of isobutylmercaptan'pn clear solution isef'o‘rmed. 115 grams*(0.'75 mole) of phenac'yl ' The compounds of this invention are readily prepared by oxidizing the corresponding sul?de chloride are addedand the mixture shaken vigor; ously. The mixture becomes warm and‘forms compounds. The sul?des‘ are made by reacting the corresponding ketone intermediates of the formula, ’ two ‘liquid’ layers." It is then re?uxed for‘about thirty 'minutes,’cooled, and diluted with two vol ' umes of water; The‘product is extracted twice with small volumes‘ of ether. The ‘extracts are 00 combined,‘ washed 'with water, saturated‘ salt solution, and dried over anhydrous magnesium <1“) sulfate. ' The ether is distilled off on‘the steam‘ where R has'the same signi?cance as in the 40', bath and the residue distilled‘at reduced pres formula given above for the ?nal products, with sure. ‘135 grams 'ofia" colorless liquid distilling an alkaline, water-soluble cyanide and'aqueous at 125°?"C. ‘at 1 mm.‘ is obtained. The yield is ammonium carbonate or the like combination 86.5% of the'theo'retical; nD2°=L5486L l ‘ ‘ “ consisting of, or capable of generating, ammonia, carbon dioxide, and water, acidifying the reac 45 tion mixture, and separating the hydantoin. In spite of the alkaline conditions used, I have found that the sul?de linkage of the intermediate ketones goes through the reaction to ‘give my new hydantoins with substantially no change. The intermediate ketones are, in most cases, pre Preparation of‘ 5-isobutylmercaptomethyl-5 phenylhydantoin.= . . ‘ ‘ l " ' - . pared by the ‘action of the sodium salt of the appropriate mercaptan' on} phenacyl chloride (T. C. ‘Whitner, Jr., and E. E. Reid; J. A. C. S. 43, 638 (1921)). They may also be prepared by the re 55, action of an acid chloride of the formula; R-—'S—'CH2COC1 where R has the same signi?cance asin the for mula given above for the ?nal product>,,with ben . 93 grams (0.45‘ mole) or p-isobutylmercap‘to-Q acetophenone', 40 grams of potassium cyanide, and 60 125 grams vof ammonium carbonate: are' mixed 2,404,510 ‘ with 1 liter of 70% ethanol in-a'2 liter,» round ‘ ~ without iconvulsive seizures'and yet being alert :7 imentallyqand p'hysically.~_ ' 1 bottom-?ask.‘ .A'large'bore aircondenser is'?tted ' to the ?a'sk which is then heated at 55-60° C. for about eight hours. Other compounds of my invention may be pre i-pared by the same methods illustrated above and ‘ steam bath. ,The residue is‘ diluted to about '1/2 using as starting materials, instead of isobutyl .mercaptan, other mercaptans, such as heptyl ' 1 orated to about 1/3 ofThe the original mixture volume is then on evap= the 1,_ ‘ of the original volume with. water and acidi?ed “ . mercaptans or, in general, mercaptans of for with concentrated hydrochloric acid ~(alloperaei ‘ i-miula, .R—S—-H, where R may be a straight, ' ‘ tions are performed in the :hood); An'.oilipre-'v " branched, “or cyclic alkyl radical or an aryl or ‘ cipitates which quickly solidi?es. ‘The solid is v10 aralkyl radical such‘ that the total number of. car bon atoms in His not more than 7. 3 solution. The resulting solution 'is charcoaled‘f; '. Further examples of my newihydantoins which I have prepared by methods such as'described 3 and ?ltered. The ?ltrate is acidi?ed with hy-_ . above for the 5-isobutylsulfonomethyl compound ‘I drochloric acid, cooled, and ?ltered. The solid 7 ‘ ?ltered off and dissolved in 5% sodium ‘hydroxide ‘ material is recrystallized from ethanol. are the following, wherein R stands forthe rad The I ical RzOf ‘the ‘general-‘formula, yield is'193 grams of 774.5% of thevtheoretical. ‘I 1 Y 'Preparationi-of . 5 -—isobutylsulfonomethy1 e5 ‘ phenylhydantoin. E 20 . '0 Ha lvltethylunli _________________ _ _ 30 20.8 ‘grams (0.75 mole) of. 5-isobuty1mercaptoe ,7 methyl-Smhenylhydantoin are added to a solui ' 1. ,tion of 150 .cc.’ of glacial acetic acidand 38cc. ‘ of acetic .anhydride' vin‘a small Erlenmeyer ?ask. I ' quickly forms and‘fgradually warms up. ~ When 40 ‘ the temperature-of thesolution' reaches FIG-75°C. . " The" sul?de, intermediates corresponding to leach the above: listddisulfones, withjinelting, points 38 cc. of 30%- hydrogen peroxide are then ‘added ._ of in each instance, are" givenlin ‘my .copending ,ap and . the- mixture shaken gently. A solution i plication. , A Other compounds of my invention maybesimia 7 larly prepared having v.alkyl radicals such as Qthe' ?ask -_isplaced in an icewater bathin-order isecondary-butyl, .1 -methylbutyl, .1 -methylamyl, ‘ to keep .the'temperature below.80°,C. When‘ the e, l-ethylamyl, or l-methylhexyl as the substituent 1 reaction has slowed down,‘ the "flask 'is‘removed =' represented by R in the general formula. I prefer ‘ from ‘the ice water-bathand allowed ‘to stand 45 V thebranched chainalkyl derivatives. for an hour. The reaction products are trans; . -.The sodium salts ,of the above listedhydan ; ferried-t0 alargerflask anddiluted to, ?ve volumes , toins are prepared'by reacting thehydantoin with The desired-hydantoin precipitates ‘ with water. sodium hydroxide as set ‘forth iin the example as :a; --sol;i‘d.‘ ,After cooling to corrlpletethepre cipitation, ‘ithe :mixture .is filtered. The :solid'iis 50 given for the isobutyl derivative. Other salts are washed :with water ‘and recrystallized. from 95% . 1 ethanol; "The *yieldxis .121 grams orx-90% :ofrthe \ , theoretical. found, 8.87. P;;:221° C. :- ' % N: Calc-’d.,'9:0.3; prepared by using, insteadjof sodium hydroxide, ammonium hydroxide'or an amine to obtain the corresponding salts indicated’ in the general formula under the symbol M. > The compounds of my invention, either in the _A1 quantity oftthe hydantoin of this example 55 form of the hydantoins ortheiresalts, may be i is dissolved ;in a solution of :one equivalent of administered orally or'parenterally, as by injec , dilute :sodium hydroxide solution; ‘Thesolution 1 tion.v They can be suspended or dissolved in inert is then treated with charcoal todecolorize and carrier liquids such as in aqueous solution'or in I clear up thesolution- The mixture ‘with char suspension in animal or vegetable oils or fats 1 coal is?ltered and ‘the ?ltrate evaporated todry before administration. ,1 ness under reduced pressure at about50° C. ‘The ~What I:.claim aslmy invention is: 3 dry solid obtained is the sodium salt of '5-iso l.’ A compound having the formula, ; butylsulfonomethyl - 5 - phenylhydantoin having 1 the formula, ' . 7 - ' ' . 65 CH: . ' CRYHALO .70 where Ris a member of ‘the class alkylgcycloa 1 This sodium salt is-an effective anticonvulsant I alkyl, aryl, and ara-lkyl radicals having not more ‘ whengiven orally anddoes not act as a hypnotic. than 7 carbon atoms, andM is a member of the This isnn advantage, for example where .a vperson ‘ desires to'carryon his daily tasks onemployment groupconsisting [of hydrogen and non-toxic isalt .75 forming groups. : . - 2,404,510 2. A compound having the formula, which comprises oxidizing a hydantoin of formula R-s-oH, I oo-NH with an oxidizing agent for converting an organic sul?de to the corresponding sulfone, where R is where R is an alkyl radical having not more than va member of the class alkyl, cycloalkyl, aryl, and , 7 carbon atoms and M is a member of the group aralkyl radicals having not more than '7 carbon consisting of hydrogen and non-toxic salt-form 10 atoms. 7. Process for obtaining hydantoin compounds ing groups. which comprises oxidizing a hydantoin of formula 3. A compound having the formula, I R-S-CH: with an oxidizing agent for converting an organic sul?de to the corresponding sulfone, where R is where R is a branched chain alkyl radical hav 20 a branched chain alkyl radical having not more ing not more than 7 carbon atoms and M is a than 7 carbon atoms. member of the group consisting of hydrogen and 8. Process for obtaining hydantoin compounds non-toxic salt-forming groups. which comprises. oxidizing 5-isobutylmercapto 4. 5-isobutylsulfonomethyl-5-phenylhydantoin. methyl-?-phenylhydantoin with hydrogen per 5. The sodium salt of 5-isobuty1sulfonomethyl 25 oxide to convert said hydantoin to 5-isobuty1 ?-phenylhydantoin. 6. Process for obtaining hydantoin compounds sulfonomethyl-5-phenylhydantoin. ' LOREN M. LONG.