Note: Descriptions are shown in the official language in which they were submitted.
-- 1
4-13767
Sub~tituted thiazolidin~l ester~ of mineral acid~
'~he in~ention rclate~ to novel sub~tituted thia~
zolidi~yl ~ster~ o~ mineral acid3 and to salt~ o~ ~uch
~ompounds haYing valuable pha~macologic~l properties, to
proce~ses ~or the manu~acture o~ these novel sub~tances,
to pharmaceutical preparations that contai~ ~hese sub-
stance~ a~d to the u~e o~ the~e sub~tances and prepara-
tion~ contalning them.
The compound~ according to the inYe~tion corre~pond
to the general ~ormula
Il 12
0~ . . CO
R~ ¦ I I I/R4 (Ij
/ ~ ~C-N7~ C!\ C~
in wh~ch one o~ the ~mbols ~ and R2 represent~ an alkyl
radical that ha~ 3 or 4 carbo~ atoms and i~ unsaturated
in the 2,3 posltion9 and the other repr~ents ~uch a
:,.' ~
radical or lower alk~rl 9 R3 Qnd R4 each r~present~
illdepeIldently of the other, hydrogen or meth~l~ and
represents a radical OI the formula
/Z2
- -S0--0--Z or --P~-0
oz3
(I~) (Ib~
5 in which Zl~ or each of Z2 and Z3, independently of the
other,, represents hydrogen or lower alkyl9 or Z2 and Z3
together represent lo~er alkylene. The invention r~
late~ 30 to ~alt~ o~ cortlpound~ o~ the g~neral -formula
in which Zl .? or Z3 and optionally al~o Z2 repreæent ( ~)
10 hydrogen, wit;h base~, eGpecially to the pharmaceu~ically
acceptable ~alt~ with ba~esO
In the compound~ o~ the general formula I" an
alkyl radical Rl and/or R2 that i~ at~Lrated ~ th~
293 po~it~on contain~ a double or triple bond and i89
15 Ior e:~ample, Is.llyl 9 1~ or 2-methallyl or 2 propynyl.
A lower alkyl radical Rl or R2, and lower alkyl which
may be pre~ent a~ Zl or a~ Z2 and Z3, contains up to 7,
pre~erably up to 4, carbqn atoms and is~ for examplet
pe~tyl~ i~opentyl, laeope~yl; he~yl or ~ptyl~ or pr~-
2t) ~erably propyl, isopropyl, butyl or i~obutyl ~ bute~p~cially ethyl or, more especlally, methyl. ~ower
~lkylen~ ~ormed b~r 22 and Z3 together ha~ ~rom 2 to 5
oarbon atom~ with 3 or7 preferably~ 2 chain members
and is~ Ior e:~amplo~ propylen0~ l~ 2 dimethylethylelle "
25 trimethylene, 2 - -methyltrimethylen~ , 3- or 2, 2-di~
meth~ltr1me~h2;~1ene or, e~pecially, eth~lene,.
Salt~ with bases OI compou~ds OI the general
~ormula X that are capabl~ of ~alt ~orm~tion are, ~or
e~camp e ~ ~etal ~alt~, ~u . h a~ alkali metal ~alt~ " f`or
- 3
e~ampl~ ~odium or potas~ium 9alt8, or alkaline earth
metal ~alt~ such a~ magne~ium or calcium ~alt~, and
al~o ammonium salt~ and salts with prlmar~ 9 3econdary
or tertiary monoacidic or polyacidic or~anic ba3e~,
such a~, ~or exampls, ethylami~e, 2-aminoethanolg di
ethylamineg iminodiethanol9 tri~thylamine, 2-(dl
ethylamino)-ethanol, nitrilotriethanol or pyrid1ne,
or 1,2-ethanediamine~ The corre~ponding pharmaceuti-
cally acceptable, non ~o~ic ~alt~ are pre~erred~
Compound~ o~ the gener~l formula I having a
radical A o~ the partial ~ormula Ib can, according to
the definitio~ of Z2 and Z~ be i~ the ~orm o~ ~ither
neutral phosphoric acid e~ter~ or acidlc, that is to
~ay monoba~c (with Z2 as lower alkyl and Z3 a~ hydro-
~) or diba~ic (with Z2 and Z3 a~ hydrogen)~ pho3-
phoric acid e~ter~.
~ he compounds o~ the ~ormula I can be in the ~orm
o~ isomeric mixture~, ior e~ample mixtures oi race-
mates (dia~tereoi~omeric mixture) or racemates, or in
the ~orm of pl~e i~omer~ ~or exampl~ p~re racemate~
or optical antipode~.
~ he ~ovel compounds o~ the general formula I and
the salt~ of ~uch compounds e~hibit valuable pharma-
cologlcal properties, esp~ci~lly tumour-lnh~biting
acti~ity~ Th:Ls can ba demon~trated in test~ on animal~
for example by the oral or pare~teral~ ~uch a~ intra-
peritoneal or ~ubcutan~ous 9 admini~tration o~ do~e~ oi
betw~n 10 and 250 mg/kg in Ehrl~ch carcinoma in mice
(transplant: 1 x 106 cell~ (A~cites) iop~ to ~male
micc ~MRI)9 in Walker oarcino~arGoma 256 in rat~
(transplant: 05l~ ml o~ a Buspell~io~ oY ~ol~d tumours
in Hanks ~olution ~IIC~, or i.m. to mal~ rat~ (Wistar~),
in tr~n~plantable mammar~ adenocarciuoma R ~230 ~C in
rats (transplant: 0.5 ml o~ a su3pen~ion of ~ol~d
tumour~ in ~ank~ ~olution 8~Co or i~mO to ~emale rat~
(Flscher)) ~nd e~pecially in mammary carcinoma in rats
induced by 7,12-~dimeth~lbenz~a]anthracene (DMBA)
(induced b~ the p.o. administration o* 15 mg o~ DMBA
in 1 ml of se~ame oil to 50 day old ~emal~ rat~ (Sprague
Dawley), it being po~sible to detect multiple tumo~r~
a~ter 6 to 8 weeks~0
Thus, for e~ample, in ~hrlich carcinoma, a~ter
i~traperitoneal admi~istration 4 times (4 hours ait~r~
and then 1, 2 and 3 day~ a~t~r tr~n~plantation: ~0
animal~ per dosQ; the quantity o~ A~cites in mi i~
determined 10 day~ a~ter transplantation); in Walker
carcinosarcoma 256 9 a~ter oral or in~raperitoneal ad-
mini~tration four ti~es (1~ 2j 3 and 4 da~s a~ter
tran~plantation; 8 to 10 animals per dos¢; the tumour
welght in gr~m~ i~ determined 10 day~ a~tor transplan~
tatio~), and in mammary adenocarcinoma R 3230 AC, a~ter
oral or intraperitoneal ad~ini~tration 10 ti~e~ (5 time~
per week ~o~ two week~ commeno~ng 4 hours aiter ~rans-
plantatio~; 10 to 15 animals per do~; the tumour
weight in grams i9 de-t~rmined 20 day~ a~tsr tran~plan-
tation) 9 it i~ po~ibl~ to dete~t the ~ollowing i~hibi-
tio~ o~ tumour growth in comparison with untreated con~
trol animals:
-- 5 ~
_. ... _ _ _ . . . _
~ s~
h C~ ~ ~o ~'t ~ I
C) ~ ~rl h rl
~'0 ~
~U
H
__ _ _ - ..... . .
~ ~ O ~p~ . _~
~ O ~p ~ N l l l l I O O
~ . ,~. __ _
h o.~ o
O rl bD~ ~ ~ ~ ~~I C~ I l
~ ,n~l~ a~ ~ 1~ ~
h~ H ~
h __ _ __ . __ C)
ld ~ O O O ri o . h
3C C~ ~0 C) IS~ ~ OO-rl C~ pL l 3
_ ~ 8 __ K ~t ~e K ~ h
~ 9~
d ~ ~o ~o
~ b~ ~ ~ O ~ ~1 ~
~ ~ ~ ~ ~ U~ ~U ~ o
O rl El rl ~ ~ - -- ~ h
h ~iis O O 8 ~ C~ ~ O ~1
O Ei Lr~ 1/~ ~ i1 I I~ri IS~ U~
- ~ ~ ,. ~ ~ ---~ --- ~ 1~
i
__ ~D __ O ~1
-- 6 --
In the ca~e o~ DM:BA~induc~d mammary carcinoma9
the ~ollowing inhibition o~ tumour growt:h and o~ the
re-îormation o~ tumo~ars can be detected a:~ter treatment
for 5 week~ ( 25 individual dose~ ) and 6 week~ ( 30 i~
5 dlvidual do~es); (the figu:res giv~n show the average
~iz~ o~ all tumours in all the test animals ):
____ ___
Compoulld do~ avera~e tumour tu~our
(~ ample~ mg~kg ~ize ~trea-ted/ reduetion
untreated t~t (in per
animals) (aJ cent)
~0 ~ 10 8.C~ 1~13 ~ ~4.73 95
30 ~ 25 p~. 2.50 / 20.63 88
__ ~_ __
2~ ~ 25 i.p. 6031 / 15.97 61
25 ~c 100 p.o. 0.96 / 19.0~ 95
____ ~__
6 2~ ~ 100 p.O~ 2.1~ J 21~55 ~
______~_ __
7 30 ~ 10 8~C. 2027 / 24~8~ 91
30 X 25 plO. 6p~8 / 21.0~ 70
__ ____ _____~___ ___
3O ~ lO ~OC. 8.77 ~ 2~.27 61
30 X 25 p.O~ 6.07 / 22.27 72
___ ____ _ ~_
~ ~o x 10 ~c. 9.03 / 22.27 59
30 x 25 p.oc 5~65 / 22.27 75
_ _ _~ ~__ ~
(Method of admixlistration: s.c.: æubcut~eou~
p.o~: oral; ~.p.: i~traperito~eal; (a): the ~igure~
glv~n ~how the a~erage ~lze o~ all tumours in all tho
teæ~ animals)~
In compari~o~ h the strong tumour-lnhiblting
acti~ity~ the toxicit~ and side-ef~ects o~ ~.he compounds
according to the in~ention are low to moderate (max-
imum ~ingle do~e tolerated:~ intraperitoneal admini~-
tration: between 500 and 1250 mg/kg~ and oral admini~-
tration: more tha~ 2500 mg/kg), ~o that they can b~ used
a~ such or~ e~pecially, i~ the form o~ phar~aceutical
preparatlvns ~or the tr~atment o~ neopla~tic di~ea,~e~
inwarm-blooded animalæ by enteral, eæpecially oral, or
parenteral admînl~tratio~ o~ therapeutically effecti~e
do~e~ and e~pacially ~or the treat~ent o~ mammary
10 carci~omaO
The in~e~t~on relate~ e~pecially to tho~e compound~
o~ the gen~ral ~ormula I in which one o~ the radisal0
Rl and R2 repre~ent~ allyl or 2-methallyl, a~d the other
al~o represent~ one o~ these group~ or9 prererabl~,
methyl7 ~hil8t R3~ R4 and ~ can ha~e the me~ni~gg gi~en
under ~ormula I but A i~ e~pecially a rad1cal o~ tho
partial ~orm~la Ia i~ which æl repre~e~ts hydrogen~ or,
pre~erably9 i~ a radical of the part~al ~ormul~ Ib in
wh~h Z2 repre~ents lower aIk~l, e~pecially methyl~ and
23 represent~ lower alky~, aspecially methgl~ or h~dro-
gen, and ealt~ e~peciall~ pharmaceutically acceptable
~alt~ with ba~es~ o~ such compound~ in which Zl~ or Z3
and optionally Z~, represent(~ hydrogen9 for example
the corresponding alkali metal ~alts, æuch as the
sodium s~lt80
~ he ~nvention relateæ more e~pecially to compound~
of the formula I in which Rl repre~ents ally1 or 2=
methallyl, and R2 al~o represen~ v~e o~ the~e radicals
or~ pre~erably, meth~l9 R3 represent~ hydrogen or,
e~pecially, meth~l, ænd R4 represe~tæ hydrogen, whilst
ha~ ~h~ meaning given under formula I but ha~ e~
pecially the pre~erred. meani~gs indicated above, and in
the radical o~ the ~ormula Ib 22 i~ e~pecially methyl
and 23 i~ e~pecially methyl or hydrogen9 and 6~1t9~ e~
~5 pecially pharmaceut1cally acceptable salt~, o~ 3UC~
compound~ in which Zl' or Z3 a~d optio~ally ~2 9 repre
~ent(s) hydrogen~
The invention relates mos~ especially to the com-
pound~ and salts 9 preferably pharmaceutically acceptable
~alts 9 for example alkali metal ~alt~, cf corre~ponding
salt-~ormin~ compou~d~, described in the Example~ 9 and
more especially 3-~ethyl-2-~[5-methyl 3-(2-methallyl)-
4-oxo~5rthiazolidinylidene]_hydrazonoJ-4 o~o 5-thia~
zolidinyl hydrogen ~ulphate and ~ethyl-3-methyl~2-
[[5 methyl-~(2-methallyl)-4~oxo-2~thiPæolidi~ dene]
hydrazono]-4-o~o-2-thiazolidin~l hydrogen phosphate~ and
e3pecially their 5alts9 ~uch a~ pharmaceutically
acceptable ~alt~, such as, for e~ample, the correspond-
ing alkali metal ~alt~, ~uch as the ~odium salts~
The novel compou~ds of the general ~ormula I can
~e man~actured according to proces~ee known ~er se~
Thu~ they can be manufactured by
a) r~¢ting a co~pound o~ the ~ormula
Rl R2
OC - ~ N ~ O
3~1 l l f/R4 ( II)
c ~ =a c
H~/ \ S / \ S / 0~
~0 with a compou~d that introduce~ the rad~ca! o~ the
partial formula Ia or Ib~ or
b) in a compound o~ the ~ormula
OC ~ I N _~0
R3~ 1 1 1 ~4 (III~
~C~ ~ N=a~ ~(,
- 9 -
in which Ao repre~ent~ a radical of the formula
/
~S2-~l or -P~
(IIIa) (IIIb)
in which Yl or ~3 repre~ent~ a radlcal that can be
replaced by the group ;Zl sr O-Z~ respectivelyt or
b~ a salt form thereo~, and Y2 represent~ a rad~c~l
O~Z or a radical that can be replaced by the grou~
-Z2 or b~ a ~alt form thereof, replacing the radical
Yl or the radical ~ by the group Zl or 0-~3, reæ-
pectively, or b~ a ~alt iorm thereo~9 and opt~onallyreplaoing the radical ~2 by the group -Z2 or by a salt
~orm thereo~,
and~ i~ de~ired, converting a compound o~ the general
formula I into ~ different compou~d of the gensral
formula I9 am1~0r9 if de~ir~d9 co~verting a ~alt ob-
tai~abl~ acco:rding to the proce~3 into the ~ree compound
or into a di~:Eerent salt9 and/or con~er~ing a compound
of the formull~ I obtainable according to the proces~ ~n
which ~1' or Z~ and optionally Z2~ repre~ent(~) hydrogen
into ~ salt thereof, a~d/or9 i~ de~ircd, ~eparatin~ an
i~omer~ mixture abtainable according to tha proce~
into the i~om~r~.
Compound~ that Lntroduoe a radical o~ the formula
Ia or Ib arep for e~amplep ~ulphur trio~ide, which ma~
al~o be used i~ the ~orm o~ complexesD such as the
pyridlne complex; or compound~ of the general ~ormula~
/ o Z2
~1~ S~2 ` -~1 or X2- P\=0
o-~3
(IV) (Y~
5:~
~ 10 -
in which ~1 or X2 repre~ents reactive functionally
modifled hydro~y. The latter i~, for example9 e~pe-
cially hydroxy esterifi~d by an ~norgani.c or organic
acid, ~uch as hydro~y e~teri~ied by a hydrohalic acid
or an aryl- or alkane~ulphonic acid7 for example ~-
toluene~ulphonlc acid or methane~ or ~thane-sulphonic
acidO ~1 or X2 i~ e~pecially halogen~ such a~ bromine
a~dt e~peciall~, chlori~eO ~ tarting materials of
the ~ormula IV there come into consid~ration, for
e~ample, chloro~ulphonic acid and the lower alkyl
e~ter~ ther~of, and a~ ~tarting materials of the formula
Y~ for example, di-low~r alk~l- or lower alkylene-phoo-
phorochloridateæ or alternatively corresponding pho~-
phorobromidate~.
It i~ preferable to carry out the reactio~ with
~ulphur trio~ide ~n an inert ~ol~ent or 801vent migture
thc reaction with the sulphur trio~ide/pyridine comple~
being carried out~ for e~ample~ in methylene chloride
or dlmeth~lformamide or mi~tureæ thereo~ with pyridi~e~
and reaction~ with ~ulphur trio~ide being carried out,
~or ~ample~ in dimethyl~ormam~do. ~he reaction tem~
peratur~ are between appro~imQtely 0 and approximately
100C; the operatio~ i~ preferably carried out at room
temperature or at slightly elevated temperature~ When
u~ing the ~ulphur trioxide/pyridine comple~ there is
obtained a~ a direct reaction product a pyriainium ~alt
of compound~ of the ~ormula I which ma~ be converted
into the corresponding acid~ orp prePerably, directly
into other salt~, such a~, ~or e~ample, aIkali metal
~0 ~alt~. When u~ing sulphur trioxide, *ree a~id~ are pro-
duced which~ if desired, can be convert~d directly~
that i~ to say without prior working up~ into 3alt~,
for example alkali metal ~alts~
The reactio~of compound$ of the ~ormula II with
35 tho~e o~ the ~ormula IV or V is pre~rably carrled ou~
in an inert~ especially aprotic organic solvent, such
a~ ~or example, methyle~e chloride~ acetonitrile,
dimethylformamide or ~imethyl ~ulpho2ideg and pre-
~erabl~ in the pre~ence o~ an acid-~binding agent, ~uch
a~ a~ organic base, ~or e~ample trl-lower alkylamine~
such as ethyldii~opropylamine or triethylamine~ and
also, ~or e~ample, pyridine, or imidazole, or an alkali
metal-lo~er alkoxide, ~or example ~odium metho~ida or
etho~ide, or an inorganic ba~e, ~or e~ample ~odium or
pota~ium hydro~ide9 and i~ the pre3ence o~ a ba~ic
ion e~changer. ~he reaction temperature selected i~,
for example, betwe~n 0 and appro~imately 100C, pre
ferahly room t~mperatur0 or ~lightly elevated tempera~
ture, a~ nece~aryg the reactio~ can be carr~ed
out i~ a clo~ed ve~el and/or undar ~n inert ga~ atmos~
ph~re, such a~ a nitrogen atmosphere~
T~ starting matsrial~ o~ the ~ormula II are ~nown
~or ex~mpls ~sr~an Of~enlegung~schri~t 2 405 ~95~ vr
can be manu~actured analogou~l~ to the compound~ d~e-
cribed thereixl).
In the ~tarting material~ o~ ~he ~ormula III,radical~ Yl9 or Y3 and opt~onally Y2, are, for e~ample7
est~ri~ied hydroxy grOUp~9 such ae hydroxy groups es- -
teri~ied b~ strong acids, ~or exampla by mineral acid~,
and also b~ stro~g organic acid~9 or eth~ri~ied hy-
droxy group~, for exampl~ hydro~y group~ etheri~ied b~
aliphatic, c~cloaliphatlc~ aromatic or araliphatic
radicals, ~uch as corre~ponding option~lly substituted
hydrocarbon radical~. ~steri~ied hydroxy group~ are
~0 especiall~ halogen, such as chlorlne or bromine 7 Whilgt
etheri~ied h~dro~ group~ ar~p inter alia9 arylo~
~uch as pheno~ or ~nitrophenoxy~ or aryl-low~r al~o~y~
~uch a~S e~pecially, ben~lo~y, and also E-nitrobenzyl~
o~y, and lower alkenylo~ or e~ample allylo~ and
al~o lower alko~y, such a~ ~or e~ample~ the group~ -Z
- 12
~~2 and -OZ3~
Compound~ o~ the general ~ormula I in which ~17 or
æ3 and optlonally Z2' repre~ent(~3 hydrogen can be
obtained by hydrolysis ? such a~ b~ the action o~ water,
optionally in the ~or~ of mixtures with sui-table organic
~olvent~, euch a~ dioxan or lower alkanol~, on compounds
o~ the general formula III in which the radical~ or
Y3 and optionally Y2, represent e~-teri~ied hydro~y groups,
8UC~ as halogen~ Such co~pound~ o~ the ~ormula I can be
produced *rom starting material~ of the ~ormula III in
wh~ch ~9 Y2 and/or Y3 repre~ent ~uitably e~terifisa
hydroxy groups al~o in tha ab~ence of water9 ~or example
by transesterification9 such a~ in the case of the
action with a suitable alcohol, ~or example a-methgl~
15 ben zyl alcohol~ ~he same end product~ can be obtained,
by ba~ic hydroly~ both ~rom the a~ore-mentio~ed
starting materialæ of the general formula III and ~rom
those in which ~1~ or Y3 and optionally Y2, represent
aryloxy or aralko~y groups9 for example by the action
o~ base~ in the pre~ence of at least ~quimolar amount~
o~ water, preferably in water-containing organic ~ol-
vent~9 such a~ corresponding lower alkanols or dio~an.
~s ba~es there may be used either organîc, preferabl~
tertiary9 bases, ~uch a~ those mentioned hereinbefore,
or inorganic bases~ ~uch a~ ~odium or pota~i~m hy
droxide, it being po~ble to obtain the react~on pro-
duct~ either directly i~ the ~orm o~ salt~ or~ ~fter
treatment wit~ an acidic reagent~ in the ~orm of fre~
a~id~.
In starti~g mat~r~al~ of ~he formula IlI in which
~1~ and ~pecially Y3 and optionally Y2~ repreeent(s)
etheri~ied hydro~yD cspeciall~ lower alkoxy and more
e~pecially methoxy9 such a radical ma~ ad~antageou~ly
b~ replaced by hydro~y by mea~s o~ a nucleophilic sub-
~t~tution reaction; in this op~ration~ in a corre~pond~
-- 13 --
ing startlng material in which the two radicals Y2 and
Y3 represent etherified hyd~oxy, for example methoxy, if
desired only one of the etherified hydroxy groups can
be cleaved~ The cleaving can ba effected by treatment
of the corresponding starting material of the formula
III wi~h a suitable nucleophilic reagent, such a
reagent preferably containing a hydroxy or, especially,
mercapto group capable of being etherified or an amino
group capable of being substituted, including quater-
1~ nised. Such reagents are, inter alia, an optionallysubstituted thiophenolate compound, such as thiophenol
in the presence of an inorganic or organic base, such
as triethylamine, or a suitable urea, or, especially,
thiourea compound, such as thiourea, and also a suitabl~,
preferably sterically hindered, amine compound, such as
a corresponding lower alkylamine, for e~ample tert.-
butylamine, and also tri lower alkylamine, such as tri-
methylamine, N-lower alkyl-morpholine or -thiomorpholine,
for example N-methylmorpholine, or pyridine.
The cleaving of an ~therified hydroxy group Yl, or
Y3 and optionally Y2, can be effected also by treatment
with a strong inorganic base, such as an alkali metal
hydroxid~, fox exampla sodium or potassium hydroxide,
preferably in the presence of an alcohol, such as a
25 lower alkanol, or example ethanol, or ammonium hy- -
droxide, or with a ~uitable neutral salt, especially an
alXali metal or alkaline earth metal halide or thio-
cyanate, such as sodium iodide, barium iodide or sodium
thiocyanate, this method being suitable especially for
cleaving lower alkenyloxy groups, for example allyloxy
groups, or aryl-lower alkoxy groups, for example benzyloxy
groups~
Furthermore, suitably etherified hydroxy groups
Yl, or ~3 and optionally Y2, especially aromati~ally or
araliphatically etherified hydroxy groups, such as op~
tionally substitut~d phenoxy or benzyloxy, can be
~ 14 -
cle~ed by hydrogenolysi~g such as b~ treatmant with
hydrogen in the presence of a noble metal cataly~t~
such as a platinum or palladium catalyst 9 it being
necessary to take care that a lower alk~nyl group ~ or
R2 18 not also reduced.
Furthermore~ in starting materials of the formula
III, esterified hydroxy ~roups Yl~ or Y3 and optionally
Y2, suoh a~ halogen7 can be replaced by lower alko~y
by reacting a corresponding compou~d with a lower alkan-
ol i~ the presence o~ a ba~e u~der substantially an-
hydrou~ r0action conditions, or with a lower alkoxid~
o~ a~ alkal1, alkaline earth or earth meta~, such as a
sodi~m or potas~ium methoxide, etho~ide or tertO-
butoxideO
The above reactions are carried out in a manner
known ~ se in the abse~c~ or~ pre~erably, in the pre~
æenc~ o~ a suitable inert sol~ent, such a~ an optionally
halogenated hydrocarbon9 ~or sxample benzene or methy~
lene chloride, a lower alkanol9 ~or example methanol,
dimethyl sulpho~id~ or acetonitrile, or a solvent mix-
ture9 and customarily under mild reaction condition~,
preferably ~t te~peratures o~ between approx~mately
-10C and appro~imately 100C, especially at room
temperature or ælightly elevated temperature~ up to
approximately 50Cp i~ ~ecessary in a closed ~essel
and/or under an i~ert gas atmospher~ such as a nitro-
gen atmoæphere. The reaction product~ can be ~eparated
of~ i~ the ~orm o~ ~ree aci~s or can be co~verted direct-
ly into the ~alt~, ~or e~ample alkali metal ~alts~
Starti~g materials o~ the ~ormula III in ~hich Y
or ~3 and optio~ally Y2; repreæent(~) an etheri~ied
hydroxy group~ such a~ lower alkox~, arylo~y or aryl~-
lower alko~y~ ca~ be manufacturad in accordance w~th
p~oceæs a)~
It i~ al~o po~sible to obtain analogouæly to pro~
15 ~
cess a3 starting material~ of the ~ormula III ln which
~1~ or Y~ and optionally Y2~ represent(s~ e~terified
hydro~y, especially halogen~ such as chlori~e, by rea~-
ting a compound o~ the ~ormula XI under mlld reaction
condltions, for e~ample 9 with an equimolar amou~t o~
~ulphuryl chloride or phosphoru~ o~ychlorid~ Th~
compound~ o~ the ~ormula III obtainabls in thi~ manner
are pre~erably ~urther reacted dir~ctly,in accordanc~
with pro~eæ~ b)J ~or example by treatment with water or
a water~containi~g organic ~olvent,to form compounds o~
the ~ormula I i~ which Zli or Z~ and Z2~ repre~ent(~)
hydrogen, or salt~ thereo~, or9 ~or ex~mple, by treat~
ment with alkali metal~lower alkoxide~; such a~ sodium
methoxide ox etho~ideg to form compound~ o~ the ~ormula
I in which Zl~ or Z3 and optionally Z27 repre~ent(s)
lower alkyl~
Compound~ o~ the ~ormula I obtainable acoording to
the i~entlo~ can be oonverted into dif~erent compou~d~
o~ the ~ormul~ I ln a manner known ~r se. Thu~, in
accordance with the above proce~ modi~ca~on b),
compou~ds o~ the formula I i~ which A ha~ -the partial
~ormula Ia o:r, e~peciall~, Ib~ and Zl or Z2 represent~
lower alkyl and Z~ repre~ents hydrogen or lo~er alkylg
a lower alky:l group Zl or Z2 repre~enting especially
~ethylp can be converted into compounds of the formula
I in which -the ~adical A ha~ the partial fo~mula Ia or
Ib in which Zl or Z~ repre~ent~ hydrogen and Z~ repre-
eents hydrogen or lower alkylG
Furthermore, i~ compo~nd~ of t~e formula I havi~g
~0 ~he partial ~orm~lae I~ and Ib in which ~1~ Z2 a~d/or
Z~ rapresent hydrogen~ the~e g~oups can b~ replaced by
lower alkyl~ ~or example by tr~atment o~ the corre~
po~ding compound or a salt thereo~ with a react~ve
e~ter o~ a lower alka~ol a~d a ~tron~ acid, ~uch as a
~5 corre3ponding lower alkylhalide, for exam~le a chlorid~
bromlde or iodide, or a corresponding ars~e- or lower
~ 16 -
alkane-sulphonic acid lower alkyl ester, for example
p-toluenesulphonic acid lower al~cyl ester or methane-
sulphonic acid lower alkyl ester.
Salts of salt-forming compounds of the formula I
obtainable according to the invention can be converted
into the free compounds in a manner known per se, for
example by treatment with an acidic reagent, such as
an acid~ or into different salts by salt interchange.
Salts of compounds of the formula I that are suitable
for salt formation, especially pharmaceutically accep-
table salts, such as, for ex~mple, those mentioned
above, can be manufactured in a manner known per se,
for example by treatment with a suitable base, such as
an alkali metal hydroxide, ammonia or a salt-forming
amine.
Mixtures of isomers can be separated into the
pure isomers in a manner known ~ se, racemic mixtures
inter alia by means of physical separation, for
example fracti.onal crystallisation or distillation, or
chromatography, inter alia high pressure li~uid
chromatography, and racemates inter alia with the
formation of ~alts with optically active bases and
~eparation of the resu].ting salt mixtures, for example
by fractional crystallisation.
The invention relates also to those embodiments
of the process in which a starting material is formed
under the reaction conditions, or in which a reactant
is optionally in the form of its saltsO
The starting materials used for carrying out the
reactions according to the invention are advantageously
those which result in the groups of end products given
special mention at the be~inning and especially in the
end products specifically described or pointed outO
I'he present invention relates also to the use of
the novel compounds as pharmacologically active, es-
pecially as carcinostatically active, compounds. The
~ 17 -
daily do~es o~ ~uch compounds are, for mammal~, depend
ing upon specie~ age, individual condition, and on the
method of ~dmini~tration~ between appro~imately 2 mg
and approximately 250 mg, eapecially between appro~
mately 5 mg and appro~lmately 100 mg, per kg body weigh~
and within this range the doses in the case o~ paren
teral admini~tration, ~or examplc intramu~cular or ~ub
outaneous in~ectio~, or intravenou~ infu~ion~ ar~
generally lower th~n in the ca~e of enteral~ that i~
lQ to ~ay oral or rectal, administration~ ~he compounds
oi the formula I and pharmaceuticQlly acceptable salt~
of ~uch compound~ having salt-~or~ing propertie3 ar~
u~ed orally or rectally pre~erably in dosag0 unit form~
~uch a~ tablet~ dragées or capsule~ or ~uppositorles,
~nd parenterally e~pecially in the ~orm o~ in~ectable
~olutions, emul~ion~ or u~pensio~ or i~ the ~orm o~
in~u~ion ~olution~9 there coming into con~ideration as
~olution~ e~peciall~ ~olutio~ of ~alts.
The in~ention relate~ al~o to pharmaceutic~l pre~
paration~ -~or cnteral, for example oral or reotal, or
parenteral admini~tration, which contain a therapeu;
tically ei~ecti~e amol~t o~ a compound o~ the ~ormula
I or a pharmaceutically acceptable ~alt o~ such a com-
pound having salt-~orming properties, optio~ally to-
gether ~ith a pharmacouticall~ ~cceptable carrier orcarrier mixture~ it bein~ possible ~or the~e carrisr~
to be inorganic or organic, and solid or liquid~
~orresponding dosage unit ~orms, e~pec~ally for peroral
u~e~ ~or e~ample drag~e~y tablets or capeules~ pre-
~erabl~ contain ~ro~ ap~roYimately 50 mg to appro~i-
~tely 500 mg, especiall~ ~rom approximatel~ 100 mg
to approximately 400 mg, o~ a compou~d o~ the fOr~UlQ
I or a pharmaceut~cally acceptable Balt Q~ a corres-
ponding eompound that i~ capabl~ o~ ~alt ~ormation to~
gether with pharmaceutically acceptable carriers~
Suitable carriers are e~pecially ~illers, such a~
- 18 -
sugar, for example lacto~e 9 saccharose, m~nnitol or
~orbitol, c~llulose preparation~ and/or calcium phos~
phate3, ~or example tricalcium pho~ph~te or calcium
biphosphate, al~o binder~g such a~ starch pastes using,
for example, maizeV wheat, rice or potato starch~
gelatlne, tragacanth, meth~lcellulo~e and~or, if d~
sired, di~integrator~9 ~uch a~ the abo~e-mentioned
starche~, also carboxy~ethyl ~taroh, cro3~-linked
polyvinylpyrrolidone, agar, alginic acid or a ~Qlt
thereof, ~uch as sod~um lgi~ate~ Adjunct~ are e~-
pecially flow-regulating agent~ and lubricant~ ~or
example silica, talc9 stear~c acid or salts thereo~9
~uch as ma~ne~ium stearate or calcium stearate7 and/or
polyethylene glycol. Dragee cores can be provlded with
~uitable coating~ that are optlonally resistant to
ga~tric juice~g there being used, la~ alia; concen~
~rated sugar ~olution~ wh~ch may contai~ gum arabic~
talc~ polyvinylp~rrolido~e, pol~ethyle~e glycol and/or
titanium dioxide, or lacquer solution~ in ~uitable
organic ~olv~nt~ or solve~t mi~ture~ or, ~or the pro-
ductio~ of coating~ that are resistant to gastric
juiee~, solutiona o~ suitable cellulo~o preparation~,
such a~ acet~:lcellulose phthalate or hydroxypropyl
methylcellulol3e-phthalate. D~es or pigment~ may be
added to the tablet~ or dragee coati~gsD ~or egample
for idanti~ication purpose~ or to indicate diiferont
do3e~ 0~ a~t~ve ingredientO
Further pharmaceutlcal preparatio~s for oral
administratlo~ are dr~-~illed cap~ulea con~i~ting o~
gelatin~ a~d al~o ~oft~ sealed cap~ules con~i~ting o~
g~latine and a plasticiser~ ~u¢h as gl~cerine or sor-
bitol. The d~y~illed capsules may co~tain th~ ~ctive
ingredient in the ~o~m of a granulate~ ~or example in
admixture with fillers, such as lactoae~ bi~d~r~; such
a~ starehe~p and~or glid~nts~ ~uch as talc or magne
8ium ~tearate 9 and optionally ~tabili~er~ e In ~o~t
cap~ules, the active ingredie~t i5 preferably diss31ved
or ~uspended in suitable liquidsf such a~ ~att~ oil9 ~
para~in oil or liquid polyethylene glycol~ it being
po~ible al~o to add ~tabilisers~
~ rectally administrable pharmaceutical prepara~
tio~ the~e come into conæideration~ for example~
~uppo~itories which consi~t of a combination of the
active i~gredient with a ~UppoBitory base~ Suitable
suppo3itory base~ are, for example, natural or synthetic
triglycerides~ para~in hydrocarbon~, pol~e~h~lene gl~-
col~ and higher alkanole, It i~ also pos~ible to u~e
gelatine rectal capsules whlch contain a combination of
the acti~e ingredient with a baee material; as ba~e
material~ there come into co~siderat~on~ ~or examplep
liquid triglycerides~ pol~ethylene glycols and para~fin
hydrocarbons.
E~peclally 3uitable for pare~teral admini~tration
are aqueo~ solutions o~ an acti~e ingredie~t 1~ water-
~oluble ~orm, for e~ample a water- oluble ~alt, al~o
suspension~ of the active ingredie~t, such a~ corre~-
ponding oily i.~ection ~u~pen~io~, there bei~g u~ed
suitable lipoE~hili¢ ~olvents or vehicle~, ~uch as ~atty
oil~, ~or example se~ame oil, or ~ynthetic fatty acid
ester~, ~or e~:ample ethyl oleate,or triglycerid~, or
aqueous injection ~u~pensiQns that contain substance~
which increa~e the vi~co~ity, ~or example sodiu~ car-
bo~ymethylcellulose9 ~orbitol a~d/or dextran~ and,
optionally, ~tabilis~r~.
The pharm~ceutical preparation~ o~ the present
i~ention ca~ be manu~aot~red 1~ a manner ~own E~ se9
for e~ample by mea~ G~ conve~tio~al mi~in~ granulating~
¢on~ectio~i~g, di~olving a~d lyophili~ing proces~e3.
~hus pharmaceutical prepara~io~l~ for oral use can be
o~tained by mi~I~g tha act~va ingredient with solid
carriers~ optio~all~ gr~nulat~ng a resulti~g mi~tur~
and, if desir2d or nece~sar~ after the addit~on o~
- 20 -
suitable adjuncts~ proces~i~g the mixture or granulate
to form tablet~ or dragée core~.
The ~ollowi~g Example~ illu~trate the invention
de~cribed abo~ but do not restrict the scope oi the
invention in any way~ Temperature~ are glven in degree~
Cent~grad~.
~ a
56 g (0.35 mol) of ~ulphur trio~ide/pyridine com-
ple~ are added to a ~olution o~ 32.8 g (0~1 mol~ o~
5-hydrox~-3 methyl-2 ~[5-~athyl-3-(2-methallyl)-4-oxo
2-thiazolldi~ylidene] hydrazono~-4-thiazolidinone in
700 ml o* ~ethylene chloride and 200 ml Or anhydrous
pyridine a~d the mixture ls ~tirred at 20 25 ~or 20
hour~, The~ 700 ml of water ~re add~d and the mixture
is st~rred for a further 20 minute~ and the two layer~
are ~eparatedc ~he methylene chloride solutio~ i3
dried over magne~ium sulphate and oo~centrated by evap
oration in a water-jet vacuumg 500 ml o~ diethyl ether
are added ~o the residue and the yello~ reaction pro-
duct that precipitates out i~ filtered with ~uction andwashed three time~ with acetone and then with diethyl
ether. Th~ resulting pyridinium [3-methyl-2-[[5-methyl-
3-(2-methallyl)-4-oxo-5-thiazolidi~ylide~e~ hydrazono]-
4-o~o--5 thiaæolldinylJ sulphate melts at i87~.
~5 For conver~ion into the ~o~ alt~ 48,,7 g
(0~10 mol~ of the above pyridini~am salt are dis~olYed
in 1100 ml o~ meth~lene ~hloride and 100 ml o~ methanol
and, while stirrin~ well, a sodium metho~ide ~olution7
prepared from 2.~ g (0~10 mol~ o~ ~odt~m and 50 ml oî
30 methanol~ :is added dropwi~e thereto and the de~ired
sodium ~alt precipitate~ outO After the addition OI
~00 ~1 o~ ether the ~alt is filtered with suctio~ and
wa~hed twice with methyle~e chlorid~y once with diethyl
etherJmetha~ol 4~1 and then wi~h etherO ~fter dryi
~5 in a hi~h vacuum at 60~7 the resulti~g ~odlum ~-meth~l~
- 21 -
2-[[5-meth~1-3-(2-methallyl)~4-o~o 2-thiazolidinyllden~]-
hydroazo~o]-4o~o 5~thiazolidi~yl~ulphato melts at
195 (~ith decompo~ition~.
~.2
In a manner analogou~ to that de~cribed in
~xample 19 u~lng as ~tarting material~ 3104 g (0~10 mol)
o~ 5-hydroxy~2 ~(3-methyl-4-oxo-2-thi~zolldinylid~ne~
hydrazono]-3 ~2-methall~ 4-thiazolidinone and 56 g
(0O35 mol) o~ sulphur trioxid~/pyridine ~omple~ ther~
i~ obtained p~r~di~ium [2-~3-methyl-4o~o~2~thiazoli~
di~ylidene)-hydrazo~ 2-methallyl~4 oxo-~-thiazoli~
dinyl]-~ulphate h~ing a melting point of 161-168;
and al~o in a manner analogous to that de~cribed in
Example 1, the corre~ponding ~odiu~ salt~ having a
melting point o~ 216 ~with decompo~ition~, iæ ~btained
irom 47.4 g (0.10 mol) of the pgridi~iu~ ~alt in 800 ~1
of methylene chloride a~d a ~odium methoxida æolutio~
o~ 2.~ g ~0.10 mol) of ~odium and 200 ~ o~ m~thanol~
~o a ~olutio~ o~ 31~4 g (Ool mol) o~ 5~;hydro~y-2-
[(3-methyl 4-oxo-2-thiazol~dinylidene)~hydrazono~
(2-methallyl)-4-thiazolidinone in 500 ml o~ ~e-thyle~
chlor~d~ a~d :100 ml o~ pyridi~e ther~ is added a sus-
p~nsion that ha3 been prepared be~rehand ~rom a ~olu-
tion o~ 23.3 g (0034 mol) o~ chlorosulphonic acid in400 ml o~ methyle~e chlorld~ by the dropwi~e additio~
of 180 ml of pyridine at a re~ction temperatur~ of ~rom
-10 to 0 under a nitrogen atmosphereO The re~ultlng
reactio~ mi~ture is ~tirred at 20-25 for ~0 ho~rs~
~0 Then 700 ml o~ water are added and the mi~tur~ ie
stirred ~or a further 20 minute~ and the two layer~ are
~eparated. Th~ methylene chloride solutlo~ i9 dried
o~er magnesium sulphate and then co~entrated by ~vap-
oration in ~ water-~et vacuu~ The resulting pyridin-
3~ ium [2 ~(3-methyl~4-oxo-2 thiazolidlnylide~e)~hydra-
; 22
zono]-3~(2-methallyl)-4-oxo-5-thi~zolidinyl~ulphate
molts at 190~191c
For conver~ion into the sodium Balt ~ 47f3 g (0.10
mol) o~ the above pyridinium ~lt are dis~olved i~ 600
ml of methylene chloride and 400 ml of dimethylformamid~
and, while stirr ~ ~ell, a 2095 % strength sodium
methoxide ~olutio~ in methanol i~ added dropwise thereto.
~he sodium salt i~ precipitated out by the addition o-
~1500 ml o~ diethyl ether; the salt i~ ~iltered with
auctlon~ wa~hed oncs wi~h a 4:1 mi~ture o~ diethyl
ether a~d methanol and then with diethyl ether. ~ter
drying under a hi~h ~acuum at 60, the aodi~m 2-[(3-
methyl-4-o~o-2-thia~olidinylidene)-hydraæono~3-(2-
methallyl)-4-oxo-5-thiazolidinyl]-~ulphat@ melta at
216 (with d~compositio~).
3~3~L
In a manner analogvu~ to that de~cri~ed in
~ample ~ uoi~g aæ ~tarting ~terials 60.1 g (0.20 mol3
of ~allyl 5~dro~y 2 [(3-methyl-4-o~o-2-thia~oli-
d~nylidene)-hydrazono]-4-thi~zolidi~one~ 46.6 ml (0~70
mol) o~ chloro~ulphonic acid and 250 ml of pyridino in
700 ml o~ metklylene chlorld~ and, for co~ver3io~ into
the ~odium ~alt9 100 ml of a 304 ~o~tr~gth sodium
metho~ide sol~Ltion in metha~ol, there i~ obta~ned sodium
[3~allyl-2-[(3-methyl-4-o~o-2~thiazolidinylidene)
hydrazono~-4-oxo-5-thiazolidinyl~reulpha~e ha~ing a
melting point o* 217 (decompoæitio~0
~a~
In a m~nner analogou~ to that de3Gribed in ~xample
1~ u~ng as ~tarting materi~l~ 68 g (0.20 mol) o~ 3-
allyl~ allyl-5-meth~l-4~oxo-2-thiazolidinylide~e~
hydrazono]~5-hydroxy-4-thi~zolidinone~ 81,6 g (O~7 mol)
of chlorosulphonic acid~ 300 ml o~ pyridine in 400 ml
of m~thylene chlorid~ an~ ~or conYer~ion into the
~5 ~odium ~alt~ 50 ml of a 7.6 ~ ~trength ~odiu~ methogida
23 -
solution in ~ethanol, there i~ obta~ned sodium [3-
allyl 2-[(~allyl-5-methyl-4-oxo-2-thiazolidinyliden~)~
hydrazono~-4-o~o-5-thiazolidin~ ulphats ha~ing a
melting point o~ 190 (decompo~ition)~
~8~gEa~ ~
While ~tirring, 21 ml (0~2 mol) of dimethyl phos
phorochloridate are added dropwi~e to a ~olut~on o~
33 g (0,10 mol) of 5-hydro~y 3-methyl.-2-~5-methyl-3
(~-~ethallyl)-4-ogo-2-thiazolidinylidene] hydr~zonoJ~
4-thiazolidinone and 43 ml o~ ethyldiisopropyl~m$ne in
250 ml o~ methyle~e chloride. ~he reaction i8 at *ir~t
~ligh-tly e~othermic and the reaction temperature i~
maintai~ed at 25 by cooling. ~fter the addition 1
co~plete~ the reaetion mixture i~ ~t~rred at room
temperature ~or a further 2 hour~0 ~he mixture ~3 the~
extr~cted by ~haki~g ~lrstly with 100 ml o~ ice-cold
2N hydrochlori~ acid and then w~th two 100 ml portio~
o~ wat~r. The m~th~lene ~hlorlde solu~ion is dried
over magne~ium sulph~te and ¢oncentrat~d by evaporation
in a wa~r~et vacuum. Dimethyl-[~methgl-2-~5-methyl-
3~ methally.1)-4-o2o--2~thiazolidinylidene]-hydrQæono~-
4 o~o 5;thiazolidinyl~-phosphate remain~ behind a~ the
residue ~nd, a~ter recrystallising once ~ro~ diethyl
ether, melt~ at 99-10~~
~3a~El~Ll
While stlrring, 56 ml o~ triethylamine are added
dropwi~e to a ~olutio~ o~ 22 g (0.05 mol) o~ dimet~yl-
~3-methyl-2~[~5-m~thyl~(2-methallyl~-4-o~o-2 thi~zo-
lidinylidene]-hydrazono~4 o~o-5-thia~olidinyl]~pho~-
~0 p~ate and 26 ml o~ thiophenol in 70 ~1 o~ dio~an~ the
reaction temp~raturs riaing to 40. The reaction mix-
ture i~ than stirred at room temperature ~or a ~urther
t~o houxs. ~h~n 400 ml o~ diethyl ether are added a~d
a heavy oil ~eparate~ out~
~hc ~ther ~olutio~ i~ decan~ed o~ and th~ oil that
- 24 -
remain~ i~ di~olved in 200 ml o~ i80prop~nol ~nd; while
~tirring9 a sodium methoxide ~olution~ prepared ~rom
1.15 g (0~05 mol) o~ sodlum a~d 30 ml of methanol, i~
added thereto~ Sodium methyl ~3-methyl~2 ~[5-methyl
3-(2~methallyl)~4~oxo-2-thiazolidinylidene]-hydrazono]-
4-o~o-5-thiazolidinyl]phosphate sepa~ate~ out~ ~hi~ i3
~iltered with suctiQn3 wa~hed with a 3mall quantity of
i~opropanol and diethyl ether and then dried in ~ high
vacuum at 60 for 15 hour~. Melting poi~t 146-150o
Thi~ product i~ a d~a~tereoisomeric mi~tur~ which
ca~ be separated into the two racemate~, ~or exa~ple
by mean~ o~ high pressure llquid chromatography UBing
a ~tationary phase o~ ~ilica gel w~th a chemically
bonded C 1~ pha~e (~or example Hibar ~iChroCart HP~C
cartridge, filled with LiChro~orb RP 18~ colum~ compo
tio~: 250 ~ 4 ~m~ b~ Merck A~, Darmstadt, ~ederal
Republic o~ Germa~y) a~d a liquid pha~e~ for ~ample a
40.40:20 mi~ture o~ metha~ol/water/0.01 molar aqueo-
~od~u~ dihydrogenphosphate.
~0
While stirring at 5 - 10, 16~7 ml ~0012 mol) o~
trieth~lamine are added dropwi~e to a susp~n~ion of
30 g (0.10 mol) o~ 2-[(3~allyl-4-ox~-2-thia~olidinyli-
dene)-hydrazo~o]-5-hydroxy-3 meth~l-4~thlazolidinone
a~d 21.7 g (0.15 mol) of dimethyl phosphorochloridate
in 250 ml o~ ~ethylene chlorlde. ~he reaction i~ sl~gh~-
ly exothermic and the ~uspended ~ubsta~ce~3 with the
e~ception of the triethylami~e h~drochloride that i~
~ormedl enter into ~olution~ When the addition is com-
~0 plete~ the reaction mi~ture iB ~tirred at room tempera-
ture for a further on~ hour~ 'l'he mi~ture i~ then e~
tracted by shaki~g fir~tly with 200 ml o~ ice-cold water
and then with 100 ml o~ ioe-cold saturated sodium bi
carbo~ate ~olution~ The methylene chloride solutio~ i~
dried over magnesium ~ulphate and concentrated undar
- 2~ ~
reduced pre~sure until crystalli~atio~ begln~g 100 ml
o~ diethyl ether are added to the .re~idue ~ld -the ~2-
~(3 allyl-4-oxo-2-thiazolidinylide~e)-h~drazono~3-
methyl-4-oxo-5-thlazolidinyl~-dime~hyl phosphate i~
~iltered with suc~on. Melti~g poin~ 1~7-148~.
The ~tarting material may be prepared as ~ollow~:
a) While ~tirring~ 17~1 g (0.10 mol) of 3-allyl-2J4-
thiazolidi~edione-2~hydra~one ~colourle~ oil, cf~ U~-
PS ~ 699 116, Exampl~ 8a) to d3~ and 8~0 g (0.11 mol)
of methyl isothio~yanate are boiled under re~lux in
70 ml o~ i~opropanol for 2 hours~ and 3-allyl-2~4-
thiazolidinedionc-2-(4-me-thyl 3;~thiosemicarbazone~
separates out in the form of a coarse cry~talline
precipitate~ ~his i~ cooled with iC~9 filtered with
~uctio~ and wa~hed with a 1~ ture o* pentane and
diethyl ether. Mel~ing point: 148-151o
b) 11~0 g (0012 mol) o~glyo~ylic acld monoh~drat~
are di~ol~d in 40 ml o~ dio~an ~nd the solution i5
then diluted with 200 ml o~ carbon te~rachloride.
~heng while ~tirring~ 24.4 g (OolO mol) o~ ~allyl-
2,~ thiazolidinedione-2-(4~methyl-3 thio~emicarbazone3
are introduceld. The mixture i~ then heat~d and, with
the ~imultaneou~ dropwi~e addition of 120 ml of carbon
tetrachlQride, 120 ml of an a~@otropic mixture o~
carbon t~trachloride and water ~re di~tilled o~ in a
descendi~g conden~er. The mixture i6 cooled to 20~i
and the cry~tal mQs~ i9 dilut~d with 100 ml of dlethyl
ether; the crystal~ are ~iltered with suction and then
~hed with diethgl ether~ ~he resultin~ 2~(3~allyl~
4-oxo-2~thiazolidinylide~e3-hydrazono]-5-hydro~y 3-
methyl~4-thiazolid~none melts at 2~9~210~.
In a manner ~Lalogou~ to that described in Examplo
89 u~ing a~ starting material~ 31.4 g ~olO mol) oi
2-[(3~allyl-5 methyl~4-o~o-2-th~azolidin~lidene)-hydra-
- 26 -
zono]~5~hydroxy ~-methyl-4~thiazolidinon0~ 21~7 g (0015
mol3 o~ di~ethyl pho~phorochloridate and 16.7 ml (0.12
mol) of trlethylamine ~n 250 ml o~ methylene chlorida
there i~ obtained [2-[(3-allyl-5-methyl-4-o~o-2-thia-
zolidinylide~e)~hydrazono] 3-methyl-4-oso-5 thi~æoli
dinyl]-dimethyl phosphate h~v~ng a melting point o~
102;-107~
~ he ~tarting material i~ prepared as ~ollow~:
a) lloO g (0.12 mol) o~ glyoxylic acid monohydrate
are dis~olved 1~ 40 ml o~ dioxan and the ~olution i~
then diluted with 200 ml oY carbon tetrachloride~ ~hen,
while ~tirri~g, 25.8 g (OolO mol1 of 3-all~1-5-meth~l-
2,~-thiazolidinedione-2-(4-methyl-3-thiosemicarbazone)
[ci. U~-PS 3 699 116, Example 8a~ to e)~ are i~troduced.
The reaction mixturs i~ then heated and~ with the ~
taneou~ dropwi~e addition o~ 120 ml o~ carbo~ tetra-
chloride~ 120 ml of an azeotropic mixture o~ carbon
tetrachloride and water are distilled o~f in a de~ce~d-
ing conden~er. The mi~ture i~ cooled to 20 and the
cry~tal ma~s is diluted with 100 ml o~ diethyl ether
and 200 ml o~ penta~e, th~ crystal~ ar~ filtered with
~uctio~ and wa~hed Ni~h a 2:1 mixture o~ pentane and
dieth~l ether,, The resultlng 2-[ (3 ~allyl-5-methyl-
4-o20-2 ;thiazolidinylidene)Qhydrazono]-5hydrogy-3
methyl-4-thiazolidinone melt~ at 164-166o
While stirring~ 41,4 ml (0.30 mol) of t~iethylamlne
are add~d dropwise to a ~u~penæ~on o~ ~008 ~ (0.10 mol)
o~ 2-~(3 allyl 4 o~o~2-thiazolidin~lid~ hydrazonol-
3Q 3-methyl-4-oxo-5-thiazolidinyl]-dimethyl pho3phate and
20.5 ml (0~20 mol) o~ thioph~nol i~ 250 ml o~ i~opropanol
a~d the reaction temperature r~e~ to 30. The clear
;srellow reaction ~olut io~ then stirred at 35 ~or a
Iurther 4 hour~., Then, at ~0-~5, a so~lLn metho:Ride
35 ~olution prepared fro~a 2.~ g (OalQ mol) o~E ~odium and
~ 27 -
50 ml of methanol is added dropwise thereto, 30dium
~2-C(3-allyl-4-o~o-2-thiazolidinylidene)~hydrazono~-3-
methyl-4~oxo-5-thi~zolidinyl]-meth~l pho3phate separate~
out. Thi~ is filtered wi-th ~uc~ion and wa~hed with i~v-
propanol and dieth~l ether, A~ter recry~talli3ationfrom a 4:1 mix~ure of i~opropanol ~nd water, the product
melt~ at 200 205 (with decomposition)~
~3~.~
In a manner analogous to th~t described in Example
109 using a~ ~tarting materials 4202 g (0~10 mol) o~
[2-~(3-allyl-5 ~ethyl-4~oxo-2-thiazolidinylidene)~
hydrazo~o] 3-methyl-4 o~o 5;thiazolidi~yl~dimethyl
pho~phate, 20.5 ml ~0,2V mol) o~ thiop~e~ol and 41~4 ml
(0.30 mol) of triethyl~mine in 250 ml o~ i~opropanol
and~ ~or conver~io~ into the sodium salt9 treating the
product with 23 ml of a 10 ~ strength (w/v) methanolic
sodium metho~ide sol~tlon, there is obta~ned ~odium ~2-
~3-allyl-5 ~ethyl 4oxo-2-thia~olidinylidene) hydrazono~
3-methyl-4 oxo-5-thiazolidinyl~-methyl pho~phate h~ g
a melting poi~t o~ 190 ~decomposition)~
~:a~
While st:irr~ng and cooling at 4, a ~olution o~
0.4 g of tert.~butylamine in 5 ml of methylene chloride
i~ add~d dropw~e over a period of 7 minutes to a mix-
tur~ o~ 2.18 g o~ dimethyl ~3-meth~l 2 L~5 meth~l-3-
(2-methallyl)-4~oxo-2-thiaæolidinylidene~-hydrazono]
4-o~o 5 thiazolidinyl~ pho~phate and 12 ml o~ methyle~e
chloride under a nitrogen atmoaphere, The temperatur~
of the clear ~ellow æolution i~ allowed ~o ris~ to room
temperatur~ the ~olutlon is stirred for 3~ hour~ and
1 ml o~ tert~-butyla~ine is added. ~tirring i~ carried
out for a ~urther 16 hour~ at room temperature, a ~ur-
ther ~ ml o~ tert~but~lamin~ ar~ ~hen added t~ the
reaction mixture and ~tirring i~ continued for a
further 2~ hour~ The mixture i~ diluted with 20 ml
- 28 -
of diethyl ether and the precipitate is filtered off
and washed with a 1:3 mixture of methylene chloride and
diethyl ether and then with diethyl ether, yielding
(N-methyl-tert.-butylammonium) methyl-~3-methyl-2-~[5-
methyl-3-(2-methallyl)-4-oxo~2-thiazolidinylidene~-
hydrazono~-4-oxo-5-thiazolidinyl]-phosphate which melts
at 216 217 (with decomposition3 and which is dried at
room temperature under a high vacuum for 15 hour~. It
can be converted into the sodium salt, for example by
treatment with a methanolic sodium methoxide solution.
While stirring, a mixture of 2.2 g of dimethyl-
[3-methyl-2-~[5-methyl-3-(2-methallyl)-4-oxo-2-thia-
zolidinylidene~-hydrazono]-4-oxo-5-thiazolidinyl] phos-
phate and 0.38 g o thiourea in 2.5 ml of methanol areboiled under reflux at a bath temperature of 7G-8~
for 6 hours and a solution is produced which is left
to stand for 16 hours and which then solidifies to form
a crystal mass. This is diluted with 4 to 5 ml of
diethyl ether, and the solid material is crushed, fil-
ter~d o~f and washed with a 2:1 mixture of diethyl
ether and methanol and then with diethyl ether. The
resulting (S-methyli~othiuronium~ methyl-~2-methyl-2-
[[5-methyl-3-(2-methallyl)-4-oxo-2-thiazolidinylidene]-
hydrazono]-4-oxo-5-thiaæolidinyl]-phosphate melts at
189-191 ~with decomposition) and can be converted into
the sodium salt, for example by treatment with a
methanolic sodium methoxide solution~
While stirring, 120 ml of lN hydrochloric acid are
added to a solution of 49.4 g of ~odium methyl-[3-
methyl-2-[[5-methyl 3-(2~methallyl~-4-oxo-2-thiadia~
zolidinylidene~-hydrazono~-4-oxo-5-thiazolidinyl]-phos-
phate in 800 ml of water ~deionised). A thick semi-
gelatinous mass is produced which is dissolved in 1500 ml
,~ .
-- 29 -.
o~ dio~an at 30-35. The solution i~ diluted with
2500 ml o~ methylene chloride; the mixture is shaken
and the layers are allowed to separa-te. The aqueous
phaæe i~ separated O.-I and extracted twlce using 200
5 ml OI methylene chloride each time, The comb~ned
organlc ~olutions are wa~hed on~e with 400 ml o~ a 1:1
mixture o~ a concentrated aqueou~ sodium chloride solu
tion and with water and dried over 200 g of mag~e~ium
~ulphate for 5 minut~3. ~he mi:~ture i9 filtered~ washed
with ~ 1:2 mixture o~ dioxa~ and methyle~e chloride and
the ~iltrate is concentrated by e~aporation under ro-
duced pressure at a bathtemperature of 45 50 to a
volume of 800 ml and a crystalline precipitate i~ formed
which is filtered of~ and wa~hed twice with a ~m311
1~ quantity of dio~an and then wi-th diethyl ether. There
i~ thus obtained methyl-L~methyl-Z-[[5~methyl-3 (2-
methallyl~-4 oxo-2-thiazolidinylidene]-hydrazo~o~4 oxo~
5 thiazolidinyl]-hyd~ogen pho~phate which mel~ at 193-
194~
~ a~
While ~t:irring9 a suspe~sion of 7 g of methyl-
[ 3-methyl-2 ~ [ ¦ 5-methyl~ 2-methallyl ) -4-oxo-2~th~a-
zolidinylidene~-h~draæono]-4~oxo-5-thiazolidi~yl]-
hydro~en phosphate (~x~mple 1~) in 40 ml of distilled
25 water is adjusted to p~I 7 by the addition OI appro~i-
mately 4 7to ~tre~gth aqueous potas~ium hydroxide ana the
slightl~ turbid æolution is treated with approximately
005 g of acti~ated carbon and ~iltered. ~he ~lltrate
i~ concentrated under reduced pre~ure to a weight o~
~0 approximately 15 g and the ~yrup-like residue, which
co~tai~s some ~olid ~ubstanceg i~ dis~olved ln sa ml
o~ i~oprop~nol and~ while ~irring, diet~yl eth~r is
addea in portion~0 A ~iscous precipitate i~ produced~
a relati~ely large amount o~ diethyl ether is added and
the supernatant solution is decanted of~9 approxim~tel~
- 30 ~
40 ml of acetone are added to the residueg produci~g
a powder-like precipitate. Diethyl ether i~ again added
but the precipitate is not filtered and is drai~ed into
another ve~el with -the aid of acetone; 20 ml o~ i~o-
~
propanol are addsd and the ~hole iæ diluted with 150 mlo~ diethyl ether9 yielding pota~ium methyl L3-methYl-
2-~[5-methyl-3 (2~methallyl)-4~oxo-2-thiazolidinylide~e~
hydrazono~4-oxo-5-thiazolidinyl~-phosphate9 which can
now be filtered~ and which i~ dried under reduced
pre~ure at 60 ~or 24 hours. ~elting point 167~170G
(decompo~ition ~rom 177~)R
~Qa~
While ~tirring9 a suspension o~ 8 g o~ methyl~
(~m~thyl-2-[~5~methyl-3-(2-methallyl~-4-o~o 2~thia-
zolidinylide~e~ hydrazono]-4-oxo-5;thiazolidi~1]-
hydrogen phoæpha~e (Example 14) i~ 50 ml of di~tilled
w~ter i~ adju~ted to p~ 7-8 with an approximately 4 %
~trength aqueou~ ammonium hydroxide solution. The
~lightly turbid solutlo~ i~ cleared with activated car-
bo~ and ~iltered and the ~iltrate i~ concentrated underreduced press~s to a weight of 20 g~ ~his i~ diluted
with 80 ml o~ isopropanol~ and. di.ethyl ether is added
until the mixl;ure b~gin~ to become turbid~ Crystalli~a-
tion can be initiated by inoculation. The ammonium
meth~ 3-methyl~2~[[5-methyl-3 (2-methall~l) 4-oxo-2-
thiazolidinylidene3-hydra~ono]-4-oxo-5-thiazolidinyl]-
pho~phate is filtered o~f and dried in a high vacuum
at room temperature ~or 20 hours. M~lting point: 195-
197~
~0 ~
While ~tirri~gS a 5 ~ aqueous solution o* 2-hydro~y~
ethylAmine i~ addedt in portion~ to a suspensio~ o~ 1 g
of methyl-[3 methyl 2-[[5~methyl-2-(2-methallyl)~4~o~o-
2-thiazolidin~lide~e~h~dr~zono~-4~o~o-5-thiRzolldinyl~
hydrogen pho~phate (~x~mple 14~ in 10 ml o~ di~illed
31 ~ .
water until a pH value o~ 7-8 has been reached, The
~olutio~ ia cleared with 0,3 g of activated carbon,
filtered and concentrated under reduced pressura to a
weight of approximately 2 g. The ~emi-~olid re~idue i~
taken up in 7 ml o~ ab~olute ethanol, and diethyl ether
i~ added until the mixture begin~ to beoome ~urbid~ The
precipitate ~o obtained i~ dis~olved in approximatel~
20 ml o~ methanol, a ~mall qua~tity of activated carbo~
is added to the ~olution and the whole is filtered~
the now clear ~iltrate is concentrated to a volume o~
approximately 5 ml. ~he (2~hydroxyethyla~monium)
methyl-~3-methyl~2 [[5-methyl-3-(2 methallyl)-4-oxo-2
thiazolidinylidene~-hydrazo~o]-4-oxo-5-thiazolidinyl~
phosphat~ i~ c~u~ea to c~yatalli~e by tha addition o~
diethyl ether and then ~iltered o~ Melt~ng po~nt:
1~6-187.
~a~
A suspension o~ 1 g of methyl-C~-meth~1-2-~5-
meth~ 2-methally~)-4-oxo~2-thiazolidinylide~
hydrazono~4~oxo-5~thiazolidinyl]-hydrogen phosphate
(Example 14) :i~ 10 ml o~ distilled water i~ ad~u~ted to
p~ 7~8 by the addition in portions, while ~tirring~ of
a 5 % aqueous ~olution o~ tri~(2;hydroxyethyl~mine.
A clear solutlo~ i~ obtained which becomes turbid a~ter
about ~ minute~ and i9 concen~rated und~r reduced
pre3sure to a weight of ~ g. The mi~ture i~ diluted
with 20 ml of ab~olute ethanol9 ~tirred with 0~5 g o~
a¢tivated carbon and ~iltered~ ~he now clear ~iltrate
is concentrated under redu¢ed pre3sure to a weight 3
appro~imatelg 3 g~ the~tri~(2~hydroxyethyl)-ammo~ium~
m~thyl-[3-methyl ~-~L5-methYl ~;(2-methallyl)~4 oxo 2;
thlazolidi~ylidene3-hydr~æono3-4-oxo-5~thiasolidinyl~
pho~phate begin~ing to cry~talli3e. 10 ml o~ ab~olute
ethanol and~ i~ portion~ 10 ml of d~ethyl ether are
added,the ~alt is ~iltered o~ and dried under a h~h
vacuum at 40 ~or 6 hour3. M~lting po~nt: 145-146~
- 32 -
~m}~aa
~ oated tablet~ containing 300 mg o~ sodium [3-
methyl 2-[[5~methyl-~(2-methal]yl~4-oxo~2 thiazoli-
dinylidens]-hydrazono3-4-oxo-5-thiazolidinyl]~sulphat~
5 can be manu~actured as ~ollow~:
5~9$a~1Q~ ~or 10,000 tablet~
sodium ~3;methyl-2-[~5-methyl-3-
(2~methallyl)-4~oxo~2-thiazolidinyl-
idene]~hydrazono~-4~oxo-5-thiazolidinyl]-
eulphate 3000.0 g
maize starch 680.0 g
colloidal ,~ilica 200.0 g
magne~ium stea~.ate 2000 g
~tearic acid 50~0 g
15 eodium carboxymethyl starch 250.0 g
~ater qOg~
A m~xture of the sodium [3-methyl-2 [[5-met.hyl ~-
~2;;~ethallyl)~4-oxo~2~thiazolidinylide~e~-hydrazono~-4
oxo-5~thiazolidinyl3-sulphate, 50 g of maize starch and
the colloidal silica is worked into a moiæt ma~ with a
starch paste o~ 250 g o~ mai.ze starch and 202 kg oi
dem:inerali~ed water" Th~ forced through a ~ieve of
3 mm mesh width and dried at 45 in a fluidlsed bed
drier ~or 30 minutes. The dr~ granulate i~ pressed
through a ~ieve OI 1 mm mesh width, mixed with a pre-
viously ~ieved mixture (1 mm sieve) of 330 g o~ maize
starch9 the ma~nesium stearate, the stearic acid and
the sodium carboxymethyl starch and pressea into slil~tl~
curved tablats~
The tablet compact~ are coated in a co~f`ectionillg
boiler OI 45 cm diameter by uni~orm spraying for 30
minute~ with a solution o~ 20 g of shellac and 40 g o~
hydro~ypropylmethylcellulo~e (lo~ ~iscoslty) in 110 g
of methanol and 1350 g of meth~le~e chlor.ide; dryi~
is carried out by sim~ltaneousl~ blowing in Bir a~ 60~.
~ ~3
-- 33 --
Instead of the above-mentioned active ingredien
it i~ also possible to use the same amount of a differ-
ent active ingredient from the preceding Examples, such
as sodium ~3-allyl-2-~(3-methyl 4-oxo-2-thiazolidinyli-
dene3-hydrazono3-4-oxo-5-thiazolidinyl7 sulphate, di
methyl-[3-methyl-2-~ L 5~methyl-3~2-methallyl)-4-oxo-
2-thiazolidinylidene~-hydrazono3-4-oxo-5-thiazolidinyl]
phosphate, ~odium methyl-[3-methyl-2-r[5-methyl-3-(2-
methallyl3-2-thiazolidinylideneJ-hydrazono~-4-oxo-5-
thiazolidinyl]-phosphate, or (2-hydroxyethylammonium)
methyl-~3-methyl-2-~5-methyl-3-~2-methallyl)-2-
thiazolidinylideneJ-hydrazono~-4-oxo-5-thiazolidinyl]-
phosphate~
Example 20
Hard gelatine capsules are filled with, in each
case, 300 mg of sodium 3-methyl-2-r~5-methyl-3-(2~
methallyl~-4-oxo-2 thiazolidinylidene]-hydrazono]-4-
oxo-5-thiazolidinyl~-sulphate, mixed with 60 mg of rice
starch~
Instead of the above active ingredient it is also
possible to use the same quantity of sodium or (2-
hydroxymethylammonium) methyl-[3~methyl-2-~[5-methyl-3-
(2-methallyl)~4-oxo-2-thiazolidinylidene J -hydrazono]-4-
oxo-5-thiazolidinyl]-phosphate.
Example_21
Ampoules are filled with, in each case, 5 ral of
a sterile 4 % strength aqueous solution of sodium ~3-
methyl-2-~5-methyl-3-(2-methallyl)-4-oxo-2-thiazoli-
dinylidene~~hydrazo~o]-4 oxo-5-thiazolidinyl]-sulph~te
30 corresponding to 200 mg of active ingredient, and the
ampoules are sealed and examined.
Instead of the aboYe active ingredient it is also
possible to US2 the same quanti~y o~ sodium or (2-
hydroxyethylammonium) methyl-~3-methyl-2-[~5-methyl-3-
(2-methallyl~-4-oxo-2-thiazolidinylidene]-hydrazon~-
4 oxo-5-thiazolidinylJ-phosphateO
