CA1189511A - Substituted thiazolidinyl esters of mineral acids - Google Patents

Abstract

Substituted thiazolidinyl esters of mineral acids Abstract Compounds of the formula (I) in which one of the symbols R1 and R2 represents an alkyl radical that has 3 or 4 carbon atoms and is un-saturated in the 2,3-position, and the other represents such a radical or lower alkyl, R3 and R4 each represents, independently of the other, hydrogen or methyl, and A
represents a radical of the formula or

Description

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 - -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 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 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~ ~(, 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

~~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~

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~

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~

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~

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 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 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-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 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~

~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 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

Claims (11)

Claims

1. Process for the manufacture of compounds of the general formula (I) in which one of the symbols R1 and R2 represents an alkyl radical that has 3 or 4 carbon atoms and is un-saturated in the 2,3-position, and the other represents such a radical or lower alkyl, R3 and R4 each represents, independently of the other, hydrogen or methyl, and A
represents a radical of the formula or (Ia) (Ib) in which Z1, or each of Z2 and Z3 independently of the other, rspresents hydrogen or lower alkyl, or Z2 and Z3 together represent lower alkylene, and salts of such compounds in which Z1, or Z3 and optionally also Z2, represent(s) hydrogen, characterised in that a) a compound of the formula (II) is reacted with sulphur trioxide or a complex thereof, or with a compound of the general formula or (IV) (V) in which X1 or X2 represents hydroxy esterified by a hydro-halic acid or by an aryl- or alkane-sulphonic acid, or b) in a compound of the formula (III) in which Ao represents a radical of the formula or (IIIa) (IIIb) in which Y1 or Y3 is halogen, aryloxy, aryl-lower alkoxy, lower alkenyloxy or lower alkoxy and Y2 represents such a radical or represents a radical O-Z2, the radical Y1 or the radical Y3 is replaced by the group O-Z1 or O-Z3, res-pectively, or by a salt form thereof, and optionally the radical Y2 is replaced by the group O-Z2 or by a salt form thereof, and, if desired, a compound of the general formula I is converted into a different compound of the general formula I, and/or, if desired, a salt obtainable according to the process is converted into the free compound or into a different salt, and/or a compound of the formula I
obtainable according to the process in which Z1, or Z3 and optionally Z2, represent(s) hydrogen, is converted into a salt thereof, and/or, if desired, an isomeric mixture obtainable according to the process is separated into the isomers.

2. Process according to claim 1, characterised in that sulphur trioxide or a complex thereof is used to convert a compound of the formula II into a compound of the formula I.

3. Process according to claim 1, characterised in that a compound of the formula or in which X1 or X2 represents hydroxy esterified by a hydro-halic acid or by an aryl- or alkane-sulphonic acid, is used to convert a compound of the formula III into a com-pound of the formula I.

4. Process according to claim 3, characterised in that X1 or X2 represents halogen.

5. Process according to claim 1, characterised in that in a compound of the formula III in which Ao represents a radical of the formula IIIa or IIIb and Y1 or Y3 and optionally Y2 represent hydrogen, halogen is converted into a free hydroxy group by hydrolysis.

6. Process according to claim 1, characterised in that in a compound of the formula III in which Ao represents a radical of the formula IIIa or IIIb and Y1 or Y3 and optionally Y2 represent an etherified hydroxy group selected from the group consisting of aryloxy, aryl-lower alkoxy, lower alkenyloxy or lower alkoxy, the etherified hydroxy group is replaced by hydroxy by treatment with a thio-phenolate compound, an urea or thiourea compound or a sterically hindered amine compound, a tri-lower alkylamine, an N-lower alkylmorpholine or -thiomorpholine, or pyridine.

7. Process according to claim 1, characterised in that there are manufactured compounds of the formula I according to claim 1 in which one of the radicals R1 and R2 repre-sents allyl or 2-methylallyl, and the other also represents one of these groups or methyl, and R3, R4 and A have the meanings given in claim 1, and salts of such compounds in which Z1,or Z3 and optionally also Z2, represent(s) hydrogen.

8. Process according to claim 1, characterised in that there are manufactured compounds of the formula I according to claim 1 in which one of the radicals R1 and R2 repre-sents allyl or 2-methylallyl, and the other also represents one of these groups or methyl, R3 and R4 have the meanings given in claim 1, and A represents a radical of the partial formula Ia in which Z1 represents hydrogen, or represents a radical of the partial formula Ib in which Z2 represents lower alkyl and Z3 represents lower alkyl or hydrogen, and salts of such compounds in which Z1, or Z3 and optionally also Z2, represent(s) hydrogen.

9. Process according to claim 1, characterised in that there are manufactured compounds of the formula I according to claim 1 in which R1 represents allyl or 2-methallyl and R2 also represents one of these radicals or methyl, R3 represents hydrogen or methyl, R4 represents hydrogen, and A represents a radical of the partial formula Ia in which Z1 represents hydrogen, or represents a radical of the partial formula Ib in which Z2 represents methyl and Z3 represents hydrogen or methyl, and salts of such compounds in which Z1, or Z3 and optionally also Z2, represent(s) hydrogen.

10. Process according to claim 1 characterised in that a starting compound of the formula III is used wherein R1 is 2-methylallyl,R2 and R3 each represent methyl, R4 is hydrogen and Ao represents a radical of the formula IIIb in which Y2 and Y3 each represent methyl, so as to produce methyl-[3-methyl-2-[[5 methyl-3-(2-methallyl)-4-oxo-2-thiazolidinylidene]-hydrazono]-4-oxo-2-thiazolidinyl]-hydrogen phosphate or a salt thereof.

11. A compound of the general formula (I) in which one of the symbols R1 und R2 represents an alkyl radical that has 3 or 4 carbon atoms and is unsaturated in the 2,3-position, and the other represents such a radical or lower alkyl, R3 and R4 each represents, independently of the other, hydrogen or methyl, and A represents a radical of the formula or (Ia) (Ib) in which Z1, or each of Z2 and Z3 independently of the other, represents hydrogen or lower alkyl, or Z2 and Z3 together represent lower alkylene, and salts of such com-pounds in which Z1, or Z3 and optionally also Z2, represent(s) hydrogen, whenever prepared according to the process claimed in claim 1.