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Патент USA US2404510

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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.
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