CA1053683A - Thiazole derivatives and process for preparing same - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:
The present invention relates to novel thiazole deriva-tives of the general formula I

(I)

Description

The invention relates to novel thiazole derivatives of the general formula I, carrying prostaglandin side-chains, N ~ 2 R~
S ~~ ~ .

wherein Rl and R2 denote hydrogen atoms or alkyl groups, and R3 denotes an oxo, hydroxyl or acyloxy group. Furthermore the invention relates to processes for preparing these com-pounds.
Attempts are known to utilize the many-sided physio-logical effectsof prostaglandins in several fields of pharma-ceutical researches~ The effect of native prostaglandins is not sufficiently selective, and they are quickly deactivated in the organism, These drawbacks can be eliminated by the production of prostaglandin analogues of more selective effect that are metabolized slower (P. Ramwell and J. Shaw: Ann.
N. Y. Acad. Sci. 180, 10/1971/). Among the compounds struc-turally related to the prostaglandins also compounds can befound which inhibit both the biosynthesis and various effects o~ prostaglandins present in the organism (J. Fried et al.:
Ann. N. Y. Acad. Sci. 180, 38 /1971/). These compounds having prostaglandin-antagonistic effect may be valuable also from therapeutic aspects. Compounds inhibiting the metabolization of nàtive prostaglandins possess a therapeutic significance as well.
! The invention is aimed at the production of novel compounds with a structure related to that of prostaglandins, in which compounds the prostaglandin side-chains are coupled to a thiazole ring, instead of the cyclopentane ring present in native prostaglandins. These two side-chains can be

-2-' located in the thiazole ring vicinally at the carbon atoms 4 and 5.
In the course of our experiments we succeeded in synthesizing new thiazole derivatives in which a 6-carboxy-hexyl or 6-carbalkoxyhexyl side chain is coupled to the C4-atom of t~e thiazole ring, a 3-oxo-1-trans-octenyl or 3-hydroxy-l-trans-octenyl or 3-acyloxy-1-trans-octenyl side-chain is coupled to the C5-atom of the ring, and a hydrogen atom or an alkyl group is coupled to the C2-atom of the ring.
In one aspect the invention provides new thiazole der.~vatives of the general formula I

N ~ COOR2 R _ < 1 (I) S \~

wherein Rl and R2 denote hydrogen atoms or alkyl groups, and R3 denotes an oxo, hydroxyl or acyloxy group.

Compounds of the general formula I produced according to the invention have been classified as follows :

.
Rl R2 R3 Ia hydrogen or alkyl alkyl oxo Ib " " " hydrogen oxo Ic " " " alkyl hydroxyl Id " " " hydrogen hydroxyl Ie " " " alkyl acyloxy ~.

In an other aspect the invention provides methods for preparing the new compounds of general formula I.
Method a) (reaction scheme 1) comprises the following Qteps: acylating the sodium derivative of an acetoacetic .

. . . . ~ .

- : :, : -acid alkylester of the general formula II, wherein R4 denotes an alkyl group, with a 7-carbalkoxyheptanoyl chloride of the general formula III, wherein R5 denotes an alkyl group, and converting the obtained 10-carbalkoxy-2,4-diketodecane-3-carboxylic acid alkylester of the general formula IV, wherein R4 and Rs have the same meanings as above, with sodium methyl-ate into 9-carbomethoxy-3-ketononanic acid methylester of formula V, halogenating the latter compound to 9-carbomethoxy-2-halo-3-ketononanic acid methylester of the general formula VI, wherein Y denotes a halogen atom, reacting VI with a thioacid amide of the general formula VII, wherein Rl denotes a hydrogen atom or an alkyl group, hydrolyzing the obtained 4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester of the general formula VIII, wherein Rl stands for a hydrogen atom or an alkyl group, to obtain 4-(6-carboxyhexyl)-thiazole-5-carboxylic acid of the general formula IX, wherein Rl is a hydrogen atom or an alkyl group, subjecting IX to selective e~terification with an alcohol of the general formula R20H, wherein R2 stands for an alkyl group, in the presence of p-toluenesulphonic acid, converting the thusobtained 4-(6-car-balkoxyhexyl)-thiazole-5-carboxylic acid of the general for-mula X, wherein Rl is a hydrogen atom or an alkyl group and R2 is an alkyl group, into 4-(6-carbalkoxyhexyl~-thiazole-5-carboxylic chloride of the general formula XI, wherein Rl is a hydrogen atom or an alkyl group and R2 is an alkyl group, reducing XI with an alkali metal borohydride to 4-(6-carbal-; koxyhexyl)-5-hydroxymethylthiazole of the general formula XII, wherein Rl is a hydrogen atom or an alkyl group and R2 is an alkyl group, then oxidizing XII to 4-(6-carbalkoxyhexyl)-thiazole-5-carbaldehyde of the general formula XIII, wherein Rl is a hydrogen atom or an alkyl group, and R2 is an alkyl group, reacting XIII with 2-oxo-heptylidene-triphenyl-phosphorane to obtain 4-(6-carbalkoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole of the general formula Ia, wherein Rl is a hydrogen atom or an alkyl group and R2 is an alkyl group.
Method b) comprises the steps of reducing 4-(6-carbal-koxyhexyl)-thiazole-5-carboxylic chloric of the general for-mula XI, wherein Rl stands for a hydrogen atom or an alkyl group and R2 stands for an alkyl group, with lithium tri-tert.-butoxy-aluminium hydride to 4-(6-carbalkoxyhexyl)-thiazole-5-carbaldehyde of the general formula XIII, wherein Rl stands for a hydrogen atom or an alkyl group and R2 stands for an alkyl group, then reacting XIII with 2-oxo-heptylidene-tri-phenyl-phosphorane to obtain 4-(6-carbalkoxyhexyl)-5-(3-keto-l-trans-octenyl)-thiazole of the general ' ' /

-5- :

.~, . . . . .

-- 6 _ ~ormula IQ, wherein R1 i~ a h~drogen atom or an alkyl group and R2 i8 an al~yl group.
Method c) comprises the step~ Or converting~' 4-(6-carbalkoxyhex~ thiazole-5-carbaldehyde of the general formula ~III, wherein R1 is a hydrogen atom or an alkyl group, and R2 i8 an alkyl.group, with the sodium derivative of 2-oxo-heptylphosphonic acid dimethylest'er or with 2_oxo-hept~lidene-triphenyl phosphorane into 4-(6-carbalkoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole . 10 of the general formula Ia, wherein R1 is Q hydrogen atom or an alkyl group and R2 is an alkyl group, and, ir desired, ' hydr,ozyling Ia to 4-~carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole of the general formul~ Ib, wherein ~
is a hydrogen atom or an alkyl group (reaction scheme 2),.
or, if desired, reducing Ia with an alkali metal boro- ' ' ' bydrlde to 4-(6-carbalkoxyhex~1)-5-(3-hydrox~ tran~-octon~
.1 . . thlazolej; o~ the general formula Ic, wherein ~1 i8 a

3 h~drogen atom or an alkyl group and R2 i8 an alk~l group . (reaction scheme 3), or, if desired, reducing the compound ' 20 0~ general formula Ib with an alkali metal bor'ohyd~ide ~reaction soheme 4),.or hydrolyzing the compound of the i goneral formula Ic (reaction ~cheme 5) to 4-(6-carboxyhe~yl)-¦~ ' 5-(3-hvdroxy-1-trans-o~te~ thiazole Or the general ! ~ormula Id~ wherei~ R1 stands for a hydrogen~atom or an .
25 a}~yl group, or ac~lating ~he compound Or the:general . ' .~rm~la Ic (reactio~ :scheme 6) to 4-(6-carbalkoxyhe~y1)-5-.` (3-aoyloxy-1-trans-ootenyl)-thiazole o~ the general ~ormula `' Io~wherel~ R1 8tand8 for a h~1rogen atom or an alkJl 6roup and ~2 .itand~-for an al4yl g~oup.
~Q In.methodl a~'roi-s~nthesising the compounds Or the -: . . - ~ .

general formula I the starting material is an acetoacetic alkylester of the general formula II, preferably the readily available acetoacetic ethylester, and suberic acid (hexane-1,6-dicarboxylic acid).
The acetoacetic ester is converted into its sodium derivative by stirring the ester for 3-5 hours with sodium metal cut to small pieces, in a medium of anhydrous benzene or anhydrous ether. On reacting the sodium derivative of the acetoacetic ester with 7-carbalkoxyheptanoyl chloride of the general formula III prepared from suberic acid, a 10-carbal-koxy02,4-diketo-decane-3-carboxylic acid alkylester of the general formula IV is obtained. The 7-carbalkoxy-heptanoyl chloride of the general formula III is prepared by producing a semiester from suberic acid in the known way, and then heat-in the obtained 7-carbalkoxyheptanoic acid with thionyl chloride until the acid chloride of the general formula III
is formed. For the preparation of the compound of formula IV
expediently 7-carbomethoxyheptanoyl chloride, a known compound (J. Am. Chem. Soc. 78, 2451 /1956/) is used. The 10-carbal-koxy-2,4-diketodecane-3-carboxylic acid alkylester of the general formula IV is prepared by producing the sodium deri-vative of the acetoacetic acid aklylester of the general formula II and adding a 7-carbalkoxyheptanoyl chloride of the general formula III immediately to the reaction mixture.
When purifying the crude product it is of advantage to observe that on treating a 10=carbalkoxy-2,4-diketodecane-3-carboxylic acid aklyester of the general formula IV with a saturated solution of potassium carbonate or a saturated sodium solution according _ 1053683 to the method of S. Archer and M. G. Pratt (J. Am. Chem.
Soc. 66, 1656 /1944/), an alkali metal derivative isolable from the by-products formed at the formation of the compound of the general formula IV can be produced. However, the purification of the crude product is not needed from the aspect of the continuation of the synthesis because the crude product can be used directly for the preparation of 9-carbomethoxy-3-ketononanic acid methylester of the formula V.
The 10-carbalkoxy-2,4-diketodecane-3-carboxylic acid alkylester of the general formula IV is converted at room temperature on the effect of a solution of sodium methylate, as a result of a partial decomposition to acid and of transesterification, into 9-carbomethoxy-3-ketononanic acid methylester of the formula V. The crude product obtained by this reaction can be purified by fractionated distillation.
The 9-carbomethoxy-3-ketononanic acid methylester of formula V can be readily halogenated at the C2-atom enclosed between the keto group and the carbomethoxy group. Chlorination in a carbon tetrachloride medium with 1.0-1.2 moles of sulphuryl chloride proved to be favourable.
On reacting the halogenated product, 9-carbomethoxy-2-halo-3-ketononanic acid methylester of the general formula VI with thioacid amides of the general formula VII, 4-(6-carbome-thoxyhexyl)-thiazole-5-carboxylic methylester of the general formula VIII is obtained which carries hydrogen or an alkyl group on C2. Thiazole formation is completed in one hour when the 9-carbomethoxy-2-chloro-3-ketononanic acid methylester of formula VI is boiled in methanol with 1.0-1.2 moles of a thioacid amide of the , , .~3 , , general formula VII. On subjecting the crude product, obtained by the extraction with ether of the reaction mixture neutralized with sodium carbonate solution, to purification by column chromatography or preparative thin layer chromato-graphy, an analytically pure compound of the general formula VIII can be obtained.
The 4-(6-carboxyhexyl)-thiazole-5-carboxylic acid of the general formula IX which carries hydrogen or an alkyl group on C2 can preferably prepared by the direct hydrolysis of the crude compound of the general formula VIII. Hydro-lysis is carried out preferably with an alkali hydroxide.
Saponification with 2.5-3.5 moles of sodium hydroxide is completed in an ethanolic-aqueous medium at boiling temperature in 0.5-1.0 hour. The product of saponification, that is the 4-(6-carboxyhexyl)-thiazole-5-carboxylic acid of the gene-ral formula IX, which carries hydrogen or an alkyl group on C2, is purified by recrystallization.
On investigating the possibility of the trans-eQterification of the carboxyl group located in the ring and at the terminal C-atom of the chain of the compound of the general formula IX it has been found that esterification w-ith aliphatic alcohols in the presence of p-toluene-sulphonic acid as catalyst takes place at room temperature only in case of the terminal carboxyl group. This recognition is essential from the aspect of the synthesis. Namely, the free carboxyl group located in the ring of the 4-(6-carbal-koxyhexyl)-thiazole-5-carboxylic acid of the general formula X, which carries hydrogen or an alkyl group on C2 and posses-ses a protected terminal carboxyl group as obtained by the `selective esterification, can be converted into an acid chloride in a selective way.
-The acid chloride of the general formula XI is _9_ ~ . . , - ~ . - ~ - , ` - . - ':

produced by reacting the compound of the general formula X
expediently with oxalyl chloride in a benzenic medium at room temperature. However, also other known methods for the production of acid chlorides can be applied.
The 4-(6-carbalkoxyhexyl)-5-hydroxymethyl thiazole of the general formula XII which carries hydrogen or an alkyl group on C2 is obtained by reducing an acid chloride of the general formula XI with an alkali metal borohydride. Reduc-tion is carried out expediently in a dioxane medium with 1.5-2.0 moles of sodium borohydride.
The 4-(6-carbalkoxyhexyl)-thiazole-5-carbaldehyde of the general formula XIII which carries hydrogen or an alkyl group on C2 is produced by gentle oxidation of the hydroxyl group of the compound of the general formula XII. A very favourable way of carrying out this oxidation is the method of Collins et al. (Tetrahedron Letters 1968, 3363), using a chromium trioxide-pyridine complex in a dichloromethane medium.
The 4-(6-carbalkoxyhexyl)-5~(3-keto-1-trans-octenyl)-thlazole of the general formula Ia which carries hydrogenor an alkyl group on C2 is prepared by Wittig reaction from the compound of the general formula XIII. 2-oxo-heptylidene triphenyl phosphorane prepared in the way described by M.P.L.
Caton et al. (Tetrahedron Letters 1972, 773) can be favourably applied as Witting reagent. The compound of the general formula XIII is converted on the effect of 2.5 moles of 2-oxo-heptylidene triphenyl phosphorane under stirring at room temperature in 16 hours into a compound of the general formula Ia which latter can be separated from the triphenyl-phosphine oxide formed during the reaction and from theresidual excess of 2-oxo-heptylidene triphenyl phosphorane by column chromatography or by preparative thin layer . :. . . -chromatography.
According to method b), 4-(6-carbalkoxyhexyl)-thiazole-5-carbaldehyde of the general formula XIII, which carries hydrogen or an alkyl group on C2, is prepared direct-ly from the acid chloride of the general formula XI by reduc-tion with lithium tri-tert.butoxy-aluminium hydride. This reduction is carried out expediently in a medium of anhydrous tetrahydrofuran at -50 C.
According to method c), 4-(6-carbalkoxyhexyl)-thia-zole-5-carbaldehyde of the general formula XIII, which carries hydrogen or an alkyl group on C2, is converted into 4-(6-carbalkoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole of the general formula Ia, which carries hydrogen or an alkyl group on C2, by reacting with the sodium derivative of 2-oxo-heptylphosphonic acid dimethylester. The latter compound can be prepared expediently in the way described by E. J. Corey et al. (J. Am. Chem. Soc. 90, 3247 /1968/).
The 4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole of the general formula Ib, which carries hydrogen or an alkyl group on C2, is obtained by the hydrolysis of the corresponding compound of formula Ia. According to our investigation~ enzymatic hydrolysis is more favourable than chemical methods. It proved to be of advantage to apply esterase enzymes of microbiological origin, e.g. the lipase enzyme produced by the fungus Rhizopus oryzae and prepared according to Hungarian Patent Specification No. 160,109, for the hydrolysis of the compound of the general formula Ia. The enzymatic hydrolysis can be preferably carried out in a phosphate buffer of pH 7.5. To improve the dispersi-bility of the compound to be hydrolyzed it is advantageousto add gum arabic and the sodium salt of taurocholic acid to the reaction mixture. The ester group of the compound . ~

.~ . : . , .
.

of the general formula Ia can be saponified also with an alkali hydroxide. However, slight decomposition occurs even under mild conditions when the reaction is carried out at room temperature under nitrogen atmosphere. Consequently, the attainable yield is lower than that of the enzymatic hydrolysis.
The 4-(6-carbalkoxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole of the general formula Ic, which carries hydrogen or an alkyl group on C2, can be prepared from the corresponding compound of general formula Ia by reduction with an alkali metal borohydride. The ketone group of the compound of the general formula Ia is reduced in an aqueous-propanolic medium by 0.5 mole of sodium borohydride at room temperature in 2 hours.
The 4-(6-carboxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole of the general formula Id, which carries hydrogen or an alkyl group on C2, is obtained by reducing the correspond-ing compound of general formula Ib with an alkali metal horohydride. This reaction proceeds slower than the reduction of the compound of the general formula Ia; it requires at room temperature in an aqueous propanolic medium even in the presence of 2 moles of sodium borohydride about 16 hours.
The compound of the general formula Id can be produced more favourably by the enzymatic hydrolysis of the corresponding ; compound of general formula Ic. The enzymatic hydrolysis is carried out in the way already specified at the hydrolysis of the compound of the general formula Ia.
The 4-(6-carbalkoxyhexyl)-5-(3-acyloxy-1-trans-octenyl)-thiazole of the general formula Ie, which carries hydrogen or an alkyl group on C2, is prepared by esterification of the hydroxyl group of the corresponding compound of general for-mula Ic. Esterification can be carried out by known methods, . .

such as treatment with acid anhydrides or acid chlorides, as well. The hydroxyl group can be esterified under mild conditions, e.g. it can be acetylated in a pyridine medium at room temperature with acetic anhydride.
The structure ofthecompounds produced by the process according to the invention is unequivocally confirmed by the data of the IR, NMR and mass spectra specified in the following Examples.
On investigating the biological properties of the compounds of the general formula I prepared according to the invention it has been found that they have prostaglandin_ like effects on certain organs. From the aspect of therapeu-tic application it is essential that their action is more selective than that of native prostaglandins. They possess the valuable property of inhibiting the activity of enzymes inducing the decomposition of prostaglandins in the organism and thus they promote the rise of the endogenous level of pro~taglandins.
To illustrate the prostaglandin-like effect of the compounds of general formula I the effects of 4-(6-carboxy-hexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Id, Rl = H) on rat uterus and on stripes of rat stomach muscle, further on rat fat tissue are described. Muscle contractions were measured by the method of W. H. Newton (J. Physiol. (London) 79, 301 /1933/) whereas lipolysis appearing in the fat tissue was measured by the method of G. Cseh et al. (Acta Biochim.
Biophys. Acad, Sci. Hung. 8, 245 /1973/).
a) The compound used in a concentration of 0.01,ug/
ml induced the contraction of rat uterus suspended in a Krebs-Ringer solution containing 0.2 % of glucose which exhibitedno spontaneous cont~actions.
b) The compound in concentrations above 0.1,ug/ml - -increased, as a function of the concentration, the size and frequency ofthe rhythmical contractions of rat uterus suspen-ded in the physiological nutrient solution specified under point a).
c) From the aspect of the effect on the uterus the compound exhibited synergism with prostaglandins.
d) On applying the compound in a concentration of 0.001 ,ug/ml it decreased the lipolysis of the epididymal fat tissue of rats induced by 0.01 ,ug/ml of isopropylnorodrenalin.
It has been observed further that the activity of the enzyme 15-hydroxyprostaglandin dehydrogenase responsible for the inactivation of the native prostaglandins is competitively inhibited by the compounds of formula Ib and Id, such as 4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl~-thiazole and 4-(6-carboxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole. In accordance with this observation it has been experienced that the prostaglandin content of the rat uterine horn incubated at 37C in a Krebs-Ri~er solution of O.2 %
glucose content is significantly increased by adding 4-(6-carboxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Id, Rl = H) to the solution. The effect of the investigated compounds on 15-hydroxyprostaglandin dehydrogenase was determined by the method of M. A. Marrazzi and F. M.
~atschinsky (Prostaglandins 1, 373 /1972/), whereas the prostaglandin content of rat uterus by the method of N. Gilmore et al. (Nature 218, 1135 /1968j).
The process according to the invention is further illustrated by the following non-limiting Examples.
Exam~le 1 Prepa~ation of 4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, Rl = H) a) 10 Carbomethoxy-2,4-diketodecane-3-carboxylic acid ethylester (IV) Small portions of 3.45 g of metallic sodium cut to minute pieces were added in 2 hours under stirring to a solution of 19.5 g of acetoacetic ethylester (II) in 250 ml of anhydrous benzene, then stirring was continued for another 3 hours until the reaction with sodium was completed. The obtained suspension was treated under stirring with 31 g of 7-carbomethoxyheptanoyl chloride (III) added dropwise in 30 minutes. Subsequently the reaction mixture was stirred for further 30 minutes and boiled for 15 minutes. On cooling, the reaction mixture was poured onto a 10 % iced sulphuric acid solution. The benzene phase of the acidified reaction mixture wau separoted, wsshed with water ' . .
/

,/''~ ' ; ' //

/

until neutral and dried on sodium sulphate. On removing b~nz~ne by vacuum distillation, 44.5 g of a crude product containin6 10-carbomethoxy-2,4-diketodecane-3-carboxylic acid ethylester (IV) were obtained which could be w ed wlthout rurther purirication ~or the preparation of 9~
¢arbomethoxy-3-ketononanic acid meth~lester (V) according to polnt b).
10-Carbomethox~-2,4-diketodecane-3-carboxylic acid ethylester (IV) o~ analytical purity was prepared as rollows. ~he solution Or 10 g of the crude product in 40 ml Or diethyl ether was shaken with 40 ml Or saturated potassium carbonate solution. ~he pota6sium derivative of 10-carbo-~ methoxy-2,4-dlketodecane-3-carboxylic acid ethyIester ~eparated as an oil located between the ethereal and the agueous phases. On separating this oil it wa~ acidified with a 10 ~ sulphuric acid solution and the obtained ~olutio~
oxtracted with diethyl ether. The ethereal extract washed with wator until neutra} and dried on sodium sulphate. On removing ether by vacuum distillation 6.5 g of a distillation ~o~idue co~taining 10-carbomethoxy-2,4-diketodecane-3-oarboxylic ethylestor (IV)~ were obtained. ~hi~ residue was purified by preparati~e thin layer chromatography on a silica gel layer with the use of a running solvent misture of 40 ~ ethyl acetate and 60 % n-heptan~.
I~ spectrum ($ilm): ~ C~ 2990-2860~ 0-0 1735, 1705,

4 o_o 1240 cm~1 -DM~ 8p~0trum (¢al4): ~ W ~2 4.38, 4.15 (2 H? q~ J - 7.5 Hz~, -~ ~ 3~62 ~3 ~ ..8~ 3 C~2(CeO) 2~67 (2 E, t, J ~ 7 Hz~, ~ 2~28;~2 ~t ~ J - 7 Ez3, ~ CH3(C-0) 2.32 (3 H, 8),

5 ~ 1.9-1.25 (8 H, m), ~ CH3 1.~5 (3 H, ~, J =. 7.5 Hz) ppm.

b) 9-Carbomethoxy-3-ketononanic acid methylester (V) A solution of sodium methylate prepared form 3.45 g of sodium and 100 ml of anhydrous methanol was added to 44,5 g of the crude product of 10-carbomethoxy-2,4-diketodecane-3-carboxylic acid ethylester (IV). The reaction mixture was allowed to stand 16 hours at room temperature, then poured onto a 10 % iced sulphuric acid solution. The acidified aqueous reaction mixture was extracted with diethyl ether, the ethereal extract dried on sodium sulphate, then ether distilled off under vacuum. On subjecting the obtained distillation residue to fractional distillation, 22.5 g of 9-carbomethoxy-3-ketononanic acid methylester (V) were obtained.
B.p.: 160C at 0.4 torr.
Infrared spectrum (film) :~ CH 2980-2860,~C=0-1732, ~ C-O 1250 cm~l.
NMR spectrum (CC14): ~ OCH3 3.7 (3H, s), 3.62 (3 H, s), CH2(C=O) 3.35 (2 H, s), 2.6-2.0 (4 ~, m), ~ CH2 1.9-1.2 (8 H, m) ppm.
c) 9-Carbomethoxy-2-chloro-3-ketononanic acid methyl-ester (VI) The solution of 22.2 g of 9-carbomethoxy-3-ketonona-nic acid methylester (V) in 20 ml of carbon tetrachloride was cooled to -5C and the solution of 14.7 g of sulphuryl chloride in 10 ml of carbon tetrachloride was added drop-wise to the solution. The reaction mixture was stirred for 30 minutes at -5 C, then for 30 minutes at room temperature and finally for 30 minutes at 60C. On cooling, the reaction mixture was diluted with 100 ml of diethyl ether, then washed with a 5 % solution of sodium hydrogen carbonate and finally with water. On removing the solvent ~y distillation, 22.6 g of crude 9-carbomethoxy-2-chloro-3-;.

-. '' , .. - , ketononanic acid methyiester (VI) were obtained which could be used without any further purification for the preparation of 4-(6-carbomethoxy-hexyl)-thiazole-5-carboxylic acid methyl-egter (VIII, Rl = H) according to point d). The fractional distillation of the crude product yielded 17 g of 9-carbomethoxy-2-chloro-3-ketononanic acid methylester (VI) of analytical purity.
B.p. : 155C at 0.3 torr.
IR spectrum (film) :~ CH 3000-2860,~ C=O 1735, ~ C-O 1255 cm 1.
NMR spectrum (CC14) : ~ CH(Cl ) 4.7 (1 H, s), ~ OCH3 3.8 (3 H, s), 3.6 (3 H, s), ~ CH2 (C=O) 2.68 (2 H, t, J = 7 Hz), 2.25 (2 H, t, J = 7 Hz), ~ CH2 1.9-1.1 (8 H, m) ppm.
d) 4-(Carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, Rl - H) 16.8 g of 9-carbomethoxy-2-chloro-3-ketononanic acid methylester (VI) and 4.5 g of thioformamide (VII, Rl - H ) were boiled in 90 ml of methanol for one hour then methanol wa9 distilled off under vacuum, and the distillation residue was dissolved in 150 ml of 2 N hydrochloric acid. The obtained solution was neutralized with a 5% solution of sodium carbonate, saturated with ammonium sulphate and extrac-ted with 3 x 150 ml of diethyl ether. The ethereal extract was dried on sodium sulphate, then ether was distilled off in vacuum. Thus 16 g of crude 4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, Rl = H) were obtained which could be used without any further purification for the production of 4-(6-carboxyhexyl)-thiazole-5-carboxylic acid (IX, Rl = H) according to point e).

On subjecting the crude product to purification by preparative thin layer chromatography and using a silicagel layer as adsorvent and a mixture of 60 % ethyl acetate and 40 % n-heptane as running solvent, 4-(6-carbomethoxyhexyl)-,~ -18-thiazole-5-carboxylic acid methylester (VIII, Rl = H) of analytical purity was obtained.
IR spectrum (film) : ~CH 3000-2860,~ C=O 1740, 1715, C-O 1270 cm 1.
NMR spectrum (CC14) :S~ CH (thiazole) 8.7 (1 H, s) "~ OCH3 3.85 (3 H, s), 3.6 (3 H, s), ~ CH2(vicinal to the ring) 3.15 (2 H, t, J =~Hz), ~ CH2 (C=o) 2.25 (2 H, t, J = 7 Hz), CH2 1.95-1.1 (8 H, m) ppm.
e) 4-(6-Carboxyhexyl)-thiazole-5carboxylic acid (IX, Rl = H) To the solution of 16 g of crude 4-(6-carbomethoxy-hexyl)-thiazole-5-carboxylic acid methylester (VIII, Rl = H) in 50 ml of ethanol 100 ml of 2 N sodium hydroxide solution was added, the reaction mixture was boiled for 30 minutes, then acidified with 5 ~ sulphuric acid under ice-cooling.
On extracting the aqueous reaction mixture with 3 x 150 ml ethyl acetate, the extract was dried on sodium sulphate and evaporated in vacuum. Recrystallization of the obtained crude product from diethylether afforded 9.4 g of 4-(6-car-boxyhexyl)-thiazole-5-carboxylic acid (IX, Rl = H).
M,p. : 151-153 C.
t~ ~ IR spectrum (KBr) : ~ CH 3080, ~ CH 2980-2860,1~ C=O 1720cm NMR spectrum (CDC13 ~ D~iSO-d6) : ~ ~ CH (thiazole) 8.85 (1 H, s) COOH 8.65 (2 H),~ CH2(vicinal to the ring) 3.2 (2 H, t, J = 7 Hz), ~ CH2 (C=O) 2.25 (2 H, t, J = 7 Hz), CH2 1.95 - 1.0 (8 H, m) ppm.
f) 4-(6-Carbomethoxyhexyl)-thiazole-5-carboxylic acid -~- (x, Rl = H) 9.2 g of 4-(6-carboxyhexyl)-thiazole-5-carboxylic acid (IX, Rl = H) and 10.2 g of p-toluenesulphonic acid mono-hydrate were dissolved in 400 ml of methanol. The obtained .

, , --19--reaction mixture was stirred for 2 hours at room temperature, then poured onto one liter water. After saturating the aqueous solution with ammonium sulphate it was extracted with 3 x 400 ml of ethyl acetate, then the ethyl acetate extract was washed with water, dried on sodium sulphate and evaporated in vacuum. Recrystallization of the obtained crude product from a mixture of diethyl ether and n-hexane afforded 7.9 of 4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid (X, Rl = H).
M.p. : 113-114 C.
IR spectrum (KBr) ~ CH 3090,~ CH 3000-2860, C=O 1730, 1705, C-O 1260 cm~l .
NMR spectrum (CDC13) : ~ COOH 11.45 (1 H), ~CH (thiazole) 9.0 (1 H, s),~ OCH3 3.65 (3 H, s),~ CH2 (vicinal to the ring) 3.25 (2 H, t, J = 7.5 Hz), ~ CH2 (C=O) 2.3 (2 H, t, J = 7 Hz), ~ CH2 2.0-1.15 (8 H, m) ppm.
g) 4-(6-Carbomethoxyhexyl)-5-hydroxymethyl-thiazole (XII, Rl = H).
To the solution of 7.75 g of 4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid (X, Rl = H) in 100 ml of anhydrous benzene 8 ml of oxalyl chloride were added dropwise and the reaction mixture was allowed to stand overnight at room temperature, then the benzene and the excess oxalyl chloride were distilled off under vacuum. The obtained evaporation residue containing 4-(6-carbomethoxyhexyl)-thiazole-5-` carboxylic chloride (XI, Rl = H) was dissolved in 20 ml anhydrous dioxane and the obtained solution was added drop-wise, under stirring, to a suspension of 2.14 g of sodium borohydride in 40 ml of anhydrous dioxane. The stirring of t~e reaction mixture was continued for 30 minutes at room : temperature and then for further 30 minutes at 80C. When the reaction mixture cooled to room temperature, 50 ml of water were dropwise added under cooling with ice, then stirring was .

~. . . - . - - , .
.

continued at room temperature for 2 hours. Subsequently the aqueous reaction mixture was extracted with 3 x 50 ml of ethyl acetate, the ethyl acetate extract was dried on sodium sulphate and evaporated in vacuum, yielding 6.7 g of crude product.
On subjecting the crude product to purification by preparative thin layer chromatography, with the use of a silica gel layer and a mixture of 70 % ethyl acetate and 30 %
n-heptane as running solvent, 4-(6-carbomethoxyhexyl)-5-hydro-xymethyl-thiazole (XII, Rl = H) of analytical purity was obtained.
IR spectrum (film) :~ OH 3300,~ CH 2995-2860, C=O 1735, ~ C-O 1250 cm~l.
NMR spectrum (CC14)~ ~ CH (thiazole) 8.5 (1 H, s), ~ CH2(OH) 4.72 (2 H, s), S OH 4.35 (1 H), ~ OCH3 3.6 (3 H, ~ CH2 (vicinal to the ring) 2.65 (2 H, t, J = 7 Hz), d CH2 (c=o) 2.22 (2 H, t, J = 7 Hz),~ CH2 1.9-1 (8 H, m) ppm.

.

h) 4-(6-Oarbomethoxghex~l)-thi~zol~ c~rbsldeh;~e (XIII, R1 ' ~I) ~he 60lutlon Or 6.4 g o~ crude 4-(6-oarbomethoxyhex~l)-5-h~drox;srmeth~lthlszole (~2II, R1 ~ H) ln 60 ml o~ dlohloro-methane was dropwi~e. adde~, under stlrrint, to the ~olution o~ 40 g Or chromium trioxl~e-~tp~rldlne oo~le~c ln 800 ml of ~ichloromethane. .8t~rring Or the reactlon mixture wa~
continued for 30 mlnutes, then the reaction mixture was filtered and the filtrate evaporatea in va¢uum. '~he evaporation residue was treated in 50 ml of hot methanol with active carbon, the filtered methanolic solution was e:l~aporated, and the obtained 4.95 g crude 4-~6-carbo-m'ethoxyhex;~ thiazole-5-carbaldeh~de (~III, R1 ~ ~I) were recr;srstallized from dieth;gl ether.
15 M.p.: 60-62. C.
IR epectrum (l~Br): jJ ;~¢E 3090, ~ CH 3000-2850, ~ C~O 1730, 1660, L' c_o 1260 c~
1~ spectrum (ODCl3): J'C~I0 10.2 (1 E, 8), S~CH (thiazole) 9.d6 (1 ~, 8), 5 OaH3 3.7 (3 E, 8), ~ C~I2 (vicinal to the ring) 3.2 (2 E, t, J - 7.5 Ez), S CE2(C.0) 2.35 (2 lI, ~, J - 7.5 HZ), ~ CE2 2.05-1.1 (8 E, m) ppm.
~a8~ spectrum: molecular weight 255.
Ma~e number oi~ the c.~ acteri~tic ion~ (m/e): 255, 226, 224, ~2, 154, 140, 127, 126, 112, 99.
i~ Carbom~thox~he~yl)-5-(3-keto-1-trans-Qcten;~l)-~hiazole (Ia, ~1 ~ E~
' . '!I~.solution o~ 4~8 ~ of 4-~6-carbometho~arhex~
'` ` t~azole-5-¢arbalde~de (~
.
2-oxohe~?t r1idene triphell;yl phosphorane in 25 ml o~ carbon -: .3~ e*~ohloride was ~tirred under nitro~en curr~t at room .

~' .

-- 23 _ -temperature for 16 hours. During this time the 4(6-carbo-methoxyhexyl)-thi~zole-5-carbaldehyde (~III, R1 H) cOmpletely converted into 4-(6-carbomethox~hexyl)-5-(3-keto-1-trans-octenyl)-thiazole (I~ R1 ~ H). ~he latter compound was separated by column chromatography from the triphenyl pho~phine oxide formed during the reaction and from the residual excess of 2-oxoheptylidene triphenyl pho8phorane. A column prepared rro~ 200 g 9iliC acid was used for this ~eparation. Elution was carried out with mixtures of n-heptane and eth~l acetate whose conte~t of ethyl acetate was succe~sively increased. The product was eluted from the ¢olumn with n-heptane containing 25 % of ethyl acetate.
In this way 5.~ of 4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole of analytical purity (Ia, R1 H) were obtained.
r~ spectrum (fi~1m): ~ 7fCH 3080, ~ CH 2095-2860~ ~ C~ 1735, ~685-1660, V C~O 1595, v C-O 1250 cm 1.
NMR 6pectrum (CCl43:~ ~ CH ¢hiazole) 8.55 (1 H, 8)~ S C~CH
7.5~ 6.3 (2 H, q, ~ - 15 ~z), ~ OC~3 3.55 (3 ~, s), ~ CH2 -(~icinal to the ring) 2.85 (2 H, t, J - 6 Hz), ~ CH2(C~O) 2.5 (2 H~ t~ J ~ 6 Hz), 2.2 (2 H, t~ J - 6 Hz), ~ CH2 ~.95-1.1 (14 H! m), ~ CH3 0.9 (3 H, t~ J - 4 Hz) ppm.
Mass spectrum: molecular weight 351.
Ma~8 uumber of characteristic ion~ (m/e): 351, 320, 295, 280j 278j 252, 236, 223, 222, 208j 152, 138, 124.
amPle 2 Preparation of 4-(6-carbomethoxyheæyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, R1 H) 2.9 g of 4-(6-carbomethoxyhexyl)-thiazole-5-csrboxylic 3o chloride (~ 1 e H) obtained in the way de~cribed i~ poi~t .

~053683 g) of Example 1 were dissolved in 25 ml of anhydrous tetra-hydrofuran. ~o this solution cooled to -50 C a solution of 2.5 g of lithium,tri-tert.bu~oxy-aluminium hydride in 10 ml of anhydrous tetra~drofuran was added dropwise under ~tirring. ~he reaction mixture was stirred for an hour at 50 C, then allowed to take up room temperature and poured onto 100 ml of ice-water. The aqueou~ reaction mixture was extracted with 3 x 50 ml of diethylether, the extract dri~d on sodium sulphate and the solvent evaporated.
~he obtained 3 g evaporation residue which cont~ined 4-(6-carbomethoxyhex~ thiazole-5-carbaldehyde (XIII, R1 - ~) was purified by preparative thin layer chromatograph~, with the use of a silicagel layer as adsorbent and a mlxture of 40 % ethyl acetate and 60 % n-heptane as running solvent.
In ~his way 1.25 g of 4-(6-carbomethoxyhexyl)-thiazole-5-carbaldeh~de (~III, R1 ~ H) described in point h) of Example 1 were obtained.
From 4-(6-carbomethoxyhexyl)-thiazole-5-oarbaldehyde (XIII, Rl = ~) 4-(6-carbomethoxyhex~1)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, ~1 = H) was prepared in the way ~pecified in point i) of ~xample 1.
- Example 3 - Preparation of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octen~ thiazole (Ia, ~1 = CH3) : 25 : a) 2-Neth~1-4-(6-carbomethoxyh~xyl)-thiazole-5-oarboxylic acid methylester (VIII, R1 ~ CH3~
8.4 g of 9Lcarbomethoxy-?-chloro-3-ketononanic acid ;methylester (VI) and 2.5 g of thioacet~mide (VII, R1 = CH3) ~ were boiled in 50 ml methanol for one hour, then methanol - 3o was evaporated in vacuum and the evaporation residue .
. .

dissolved in 75 ml of 2 N hydrochloric acid. m e obtained solution was neutralized with a 5 % solution of sodium carbo-nate and saturated with ammonium sulphate, then extracted with 3 x 75 ml of diethyl ether. After drying the ethereal extract on sodium sulphate, it was evaporated in vacuum, affording 8.2 g of a crude product containing 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, Rl = CH3) which could be used without any further purification for the preparation of 2-methyl-4-(6-carboxy-hexyl)-thiazole-5-carboxylic acid (IX, Rl = CH3) according to point b) of this Example.
On purifying the crude product by preparative thin layer chromatography with the use of a silicagel layer as adsorbent and a mixture of 60 % ethyl acetate and 40 %
n-heptane as running solvent, 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, Rl = CH3) of analytical purity was obtained.
IR spectrum (film): ~ CH 3000-2860,~ C=O 1735, 1720, ~ C-O 1270 cm~l.
NMR spectrum (CC14) : ~ OCH3 3.82 (3 H, s), 3.6 (3 H, s) ~ CH2 (vicinal to the ring) 3.05 (2 H, t, J = 7 Hz), ~ CH3 2,65 (3 H, s),~ CH2(C=O) 2.25 (2 H, t, J = Hz), CH2 1.95-1.15 (8 H, m) ppm.
b) 2-Methyl-4-(6-carboxyhexyl)-thiazole-5-carboxylic acid (IX, Rl = CH3) The solution of a 8 g of crude 2-methyl-4-(6-carbo-methoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, Rl = CH3) in 25 ml ethanol was treated with 40 ml of 2 N
sodium hydroxide solution. The reaction mixture was boiled ~ for 30 minutes, then acidified with 5 N sulphuric acid under ice-cooling. After extracting the aqueous reaction mixture with 3 x 75 ml of ethyl acetate, the extract was dried on sodium sulp}late and evaporated in vacuum. The obtained crude product was recrystallized from a mixture of acetone and n-hexane, affording 5.3 g of 2-methyl-4-(6-carboxyhexyl)-thia-zole-5-carboxylic acid (IX, Rl = CH3).
M.p. : 147-149 C.
IR spectrum (KBr) : ~ OH (carboxylic acid) 3300-2200, C=O 1685 cm~l.
NMR spectrum ~DC~ + DMSO-d6) : ~ COOH 9.0 (2 H), ~ CH2 (vicinal to the ring) 3.08 (2 H, t, J = 7 Hz), ~ CH3 2.65 (3 H, s), ~ CH2(C=O) 2.25 (2 H, t, J = 7 Hz), ~CH2 1.95-l.l (8 H, m) ppm.
c) 2-Methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acld (X, Rl ~ CH3) 5.15 g of 2-methyl-4-(6-carboxyhexyl)-thiazole-5-carboxylic acid (IX, Rl = CH3) and 5.4 g of p-toluenesulphonic acid monohydrate were dissolved in 200 ml of methanol. The reaction mixture was stirred for 2 hours at room temperature, then poured onto 500 ml of water. On saturating the aqueous solution with ammonium sulphate it was extracted with 3 x 200 ml of ethyl acetate, the ethyl acetate extract was washed with water, dried on sodium sulphate and evaporated in vacuum. Recrystallization of the obtained crude product from a mixture of diethyl ether and n-hexane afforded 4.3 g of 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid [X, Rl = CH3).
M.p.: 106-107 C.
IR spectrum (KBr) : ~ OH (carboxylic acid) 3200-2200, C=O 1735, 1695, ~ C-O 1235 cm~l .
NMR spectrum (CDC13) : ~ COOH 11.45 (1 H), ~ OCH3 3.65 (3 H, s),~ CH2 (vicinal to the ring) 3.2 ~2 H, t, J = 7.5 Hz), CH3, 2.75 (3 H, s), ~ CH2(C-O) 2.25 (2 H, t, J = 7.5 Hz), ~CH2 2.0-1.05 (8 H, m) ppm.

d) 2-Methyl-4(6-carbome~hoxyhexyl~5-hydroxymethyl-thiazole (XII, Rl = CH3 ) To the solution of 4.15 g of 2-methyl-4-(6-carbo-methoxyhexyl)-thiazole-5-carboxylic acid (X, Rl = CH3) in 50 ml of anhydrous benzene 4.2 ml of oxalyl chloride were added dropwise, and the reaction mixture was allowed to stand overnight at room temperature, then benzene and excess oxalyl chloride were distilled off in vacuum. The obtained residue which contained 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic chloride (XI, Rl = CH3) was dissolved in 20 ml ofanhydrous dioxane, and a suspension of 1.1 g of sodium boro-hydride in 20 ml of anhydrous dioxane was added dropwise to the solution under continuous stirring. Stirring of the reaction mixture was continued for 30 minutes at room temperature and for further 60 minutes at 80C. When the reaction mixture was cooled to room temperature, 25 ml of water were dropwise added under ice-cooling to the reaction mixture, and stirring was continued for 2 hours at room temperature. Subsequently, the aqueous reaction mixture was extracted with 3 x 50 ml of ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated under vacuum, yielding 2.95 of crude product.
On purifying the crude product by preparative thin layer chromatography, using a silicagel layer as adsorbent and a mixture of 70 % ethyl acetate and 30% n-heptane as running solvent, 2-methyl-4-(6-carbomethoxyhexyl)-5-hydroxy-methyl-thiazole (XII, Rl = CH3 ) of analytical purity was obtained.
IR spectrum (film) : ~ OH 3300, ~ CH 30OO -2860, ~C=O

1735, bc-o 1255,b C-O (H) 1020 cm~l.

NMR spectrum (CC14) : ~ CH2 (OH) 4.62 (2 H, S),s OH 4-22 (1 H) ,~ OCH3 3.62 (3 H, s) ~ CH3 2.6 (3 H, s) ,S CH2 (vicinalto the ring) 2.59 (2 H, t, J = 7.5 HZ), ~ CH2 (C=0) 2.25 (2 H, t, J = 7 Hz), ~ CH2 1.95-1.1 (8 H, m) ppm.
e) 2-Methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carbaldehyde (XIII, Rl = CH3) The solution of 2.8 g of crude 2-methyl-4-(6-carbo-methoxyhexyl)-5-hydroxymethyl thiazole (XII, Rl = CH3) in 25 ml of dichloromethane was dropwise added to the solution of 16 g chromium trioxide-dipyiridine complex in 320 ml of dichloromethane. Stirring of the reaction mixture was con-tinued for 30 minutes, then the reaction mixture was filtered and the filtrate was evaporated in vacuum. After purifying the crude product obtained as evaporation residue , by pre-parative thin layer chromatography using silicagel ~ayer as adsorbent and a mixture of 50% ethyl acetate and 50 % of n-heptane as running solvent, 2.15 g of 2-methyl-4-(6-carbo-methoxyhexyl)-thiazole-5-carbaldehyde (XIII, Rl = CH3) were obtained.
IR spectrum (film) : ~ CH 2995-2860, ~ C=0 1732, 1660, C-0 1255 cm 1.
NMR spectrum (CC14) : ~ CH0 10.0 (1 H, s),~ OCH3 3.61 (3 H, s),S CH2Cvicinal to the ring) 3.0 (2 H, t, J = 7.5 Hz), CH3 2.7 (3 H, s),~S CH2(C=0) 2.25 (2 H, t, J = 7 Hz).
~ CH2 1.95-1.1 (8 H, m) ppm.
Mass spectrum : molecular weight 269.
Mass number of characteristic ions (m/e) : 269, 240, 238, 196, 168, 154, 141, 113.
f) 2-Methyl-4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-cotenyl)-thiazole (Ia, Rl = CH3) 2 g of 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carbaldehyde (XIII, Rl = CH3) and 7 g of 2-oxoheptylidene-triphenyl phosphorane were dissolved in 15 ml of carbon tetrachloride. The reaction mixture was stirred for 16 hours under nitrogen current. During this time the 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carbaldehyde (XIII, Rl = CH3) was completely converted into 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, Rl = CH3). The latter compound was separated by preparative thin layer chroma-tography from the triphenyl phosphine oxide formed during the reaction and from the residual excess of 2-oxoheptylidene tri-phenyl phosphorane. For the separation a silicagel layer was used as adsorbent and a mixture of 50 % ethyl acetate and 50%

n-heptane as running solvent. In this way 2.1 g of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-oc-tenyl)-thiazole (Ia, Rl = CH3) were obtained.
IR spectrum (film) :1 CH 3000-2860, ~ C=O 1735, 1685-1660, C=C 1592,~ C-O 1250 cm~l.
NMR spectrum (CC14) : ~ CH=CH 7.52, 6.22 (2 H, q, J = 15.5 Hz), ~ OCH3 3.61 (3 H, s), ~ CH2 (vicinal to the ring) 2.78 (2 H, t, J = 6.5 Hz), ~ CH3 2.63 (3 H, s),~ CH2(C=O) 2.5 (2 H, t, J = 7 Hz), 2.25 (2 H, t, J = 7 Hz), ~ CH2 1.95-1.1 (14 H, m) ~ CH3 0.95 (3 H, t, J = 6 Hz) ppm.

Mass spectrum molecular weight 365.

Mass number of characteristic ions (m/e) : 365, 334, 309, 294, 292, 266, 250, 237, 236, 222, ~66, 152, 138.
Example 4 Preparation of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, Rl = CH3) To a suspension of 0,45 g of sodium hydride in 5 ml of anhydrous 1,2-dimethoxy-ethane a solution of 4.12 g of 2-oxoheptylphosphonic acid dimethyl ester in 20 ml 1,2-dime-thoxy-ethane was added under stirring at room temperature.
The reaction mixture was stirred for an hour, then a solution of 1 g of 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carbal-dehyde (XIII, Rl = CH3) prepared according to point e) of Example 2, in 10 ml of dimethoxy-ethane was added dropwise, and stirring was continued for 5 hours. After dropwise, adding 30 ml of water under ice-cooling to the reaction mixture, it was extracted with 3 x 20 ml of diethyl ether. The extract was dried on sodium sulphate and evaporated in vacuum. The evaporation residue was purified by preparative thin layer chromatography, using a silicagel layer as adsorbent and a mixture of 40 % ethyl acetate and 60 % n-heptane as running solvent. The yield was 0.81 g of 2-methyl-4-(6-carbometho-xyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, Rl = CH3) of chromatographic purity.
Example 5 Preparation of 4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ib, Rl = H) .

- 31 _ To a ~uspension of 2.65 g of 4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (I~, R1 H) in 50 ml of a 0.2 M phosphate buffer of pH 7.5, 265 mg of lipa~e enz~me of an activit~ of 40 U/mg, prepared with the fungus Rhizopus or~Tzae, 26 mg of the sodium salt of taurocholic acid, and 2.6 ml of a 10 Yo solution of gum arabic were added. ~he mixture was then shaken at 25 C in a screening shaker desk at 260 revolutions,'minute and an amplitude of 2 cm for 24 hours. ~hen the reaction mixture was diluted with 100 ml of water, acidified with citric acid and extracted with 3 x 75 ml of ethyl acetate. ~he ethyl acetate extract was dried on sodium sulphate and evaporated in vacuum. The obtained 2.95 g evaporation residue were purified by chrom~tography on a column prepared with lOO g of ~licic acid, eluting with mixtures of n-heptane and ethyl acetate whose ethyI acetate c~ntent wa~ stepwise increa~ed. 4-(6-Carboxyhexyl)-5-~3-keto-1-trans-octenyl)-thiazole ~Ib, R1 = H) was eluted from the co~umn b~ a mixture consisting of 60 ~ ethyl acetate and 40 ~ ~-heptane, `affording thus 1.8 g of a product of chromatographic purity which was recryætallized from acetone.
M~p,: 67-68 C.
IR pectrum (XBr): ~ OH (carboxylic acid) 3200-2300, ~ 7~H
3095, iJ C~ 3000-2860, ~ C=O 1713, 1690, ~JC=C 1590 cm 1~
2~ NMR spectrum (CDCl3): ~ COOH 10.9 (1 H), ~ ~y CH (thiazole) 8.8 (1H~ CH=CH 7.72, 6.52 (2 H, q, J = 15.5 Hz), - S CE2 (~icinal to the ring) 2.9 (2 H, t, J = 7 Ezj, ~CH2(C-0) 2.65 (2 E, t, J = 7 Hz), 2.32 (2 H, t, J = 7 Hz), S CH2 2.05-1~1 (14 H, m), S CH3 0.88 (3 E, t, J = 6 Hz) ppm.
3o Ma~s spectrum: molecular weight 337.

.

M~s number of ch~r~ct~rl~tie ions (m/e): 337, 281, 27B, 266, 238, 236~ 223, 20~ 152.
,Exsm~le 6 ~rQ~aratlon o~ 4-~6-c~r~ox~hexyl)-5-~3-koto-1-tr~n~-octen~ thl~ole tIb, R~ ~ H) 2 ml o~ 1 N ~o~lum hydroxl~o was tropw~se ~d~ed undor ~ltrogen atmosphere and under lce-coollng to a ~olution of 175 m6 Of 4-(6-carbomethox~hex~l)-5-(3-keto-1-tran~-octsnyl)-thiazole (Ia, R1 ~ ~) in 5 ml of ethanol. ~he solution was subsequently stirred for 1.5 hours at room temperature.
~hen the reaction mixture was poured onto 30 ml of ice-water, acidified with 1 N hydrochloric acid and extracted with 3 x 15 ml of ethyl acetate. ~he ethyl acetate extract was dried over sodium sulphate and evaporated under vacuum.
~he evaporatlon residue was purified by preparative thin layer chromatography, using a silicagel layer as adsorbent and the organic phase of a mixture of 110 ml of ethyl aoetate, 50 ml of n-hepta~e, 100 ml of water and 20 ml of acetic acid as running solvent. In this way 71 mg of 2Q 4~(6-carboxyhexyl~)-5-(3-keto-1-trans-octenyl)-thiazole (Ib, R1 ~ ~) f ohromatographic purity were obtained. The m.p. and spectroscopical data of the product agreed with those ~pecified in Example 5 ~xample 7 Preparation of 2-methyl-4-(6-carboxyhexyl)-5-(3-keto-~~ lttrans-octenyl)-thiazole (Ibj R1 = CH3) ~o a sugpension of 912 mg of 2-methyl-4-(6-carbo-methoxyhexyl)-5-(3-keto_1-trans-octenyl)-thiazole (Ia, R~ - CH3) in 20 ml of 0.2 M phosphate buffer of pE 7.5, 90 mg of the Iipase enzyme specified in Example 5, 9 mg ~053683 - ~3 -of the æo~ium æalt of t~urocholic acid and 0.9 ml of a 1 '~
~o]ution of gum ar~bic were added~ The mixture was then ~haken at 25 ~C in a æcreening æhaker de~k Qt 260 revolu-tio~min~te and an amplitude'of 2 cm for 24 hours. ~en ~he reaction mixture was diluted with 50 ml of water, acidified with citric acid and extracted with 3 x 40 ml of eth~71 acetate. ~he ethyl ~cetate extract was dried o~er æodium æulphate and evaporated under ~acuum. ~he obtained 1.03gevaporation residue were puri'fied ~y preparative thin layer chromatography in the way specified in Example 6. ~hu~', 645 mg of 2-methyl-4-(6-carboxyhexyl)-5-(3-keto-1-trans-octen~ thiazole (Ib, R1 = CH3) were obtained .
; IR spectrum (film): ~OH (carboxylic acid~ 3500-2400, ~ CH 2995-2860, ~ C=O 1720, 1680, Y C-C 1590 cm 1.
NMR spectrum (CCl4): ~ COOH 10.4 (1 E), S CH-CH 7.45,

6.18 (2 H~ ~, J - 15.5 Hz), ~ CH2 (vicinal to the ring) 2.75 (2 H, t, J- 7 Hz), ~ CH3 2.65 (3 H? 8)~ ~CE2(c=O) 2.45 (2 H, t, J ~ 7 Hz), 2.25 (2 H, t, J = 7 Ez), S CH2 ' ~0 1.95-1.1 (14 E, m), ~ CE3 0.9 (3 H, t, J = 5 Hz) ppm.
Ma8s spectrum: molecular weight 351.
Mas~ number of characteristic ions (m/e): 351, 295, 292, ` 280~ 252, 250, 237, 222, 166.
~xam~le 8 ' `'' ?5 Preparation of 4-(6-carbomethoxyhexyl)-5-(3-hydroxy-trans-octenyl)-thiazole (Ic, ~1 = H) - ~he solution of 143 mg of sodium borohydride in 30 ml of water was added to the æolution of 2.65 g of 4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octen~l)-thiazole 3o (Ia, R1 = ~) in 30 ml of isopropanol. ~he obtained reaction ' ' ' ' , : - . :

mixture was stirred for 2 hours at room temperature, then poured onto 150 ml of water, and extracted with 3 x 75 ml of ethyl acetate. The ethyl acetate extract was washed with water until neutral and evaporated in vacuum. The obtained 2.5 g of residue on evaporation was subjected to chromatography on a column prepared with 100 g of silica, carrying out the elution with mixtures of n-heptane and ethyl acetate having stepwise increased content of ethyl acetate. The desired 4-(6-carbomethoxyhexyl)-5-(3-hydroxy-l-trans-octenyl)-thiazole (Ic, Rl = H) was eluted from the column with a mixture consisting of 70 % n-heptane and 30 %
ethyl acetate, affording 2.2 g of a product of chromatogra-phic purity.
IR spectrum (film) : ~ OH 3350, ~ ~ CH 3080, ~ CH 3000-2860, C=O 1735,~ C=C 1640, ~ C-O 1250 cm 1 .
NMR spectrum (CC14) : ~CH (thiazole) 8.5 (1 H, s), ~ CH=CH 6.67 (1 H, d, J = 16 Hz), 5.97 (1 H, dd, J = 16 Hz, J = 6 Hz),~ CH(OH)4.2 (1 H, m), ~ OCH3 3.6 (3 H, s), ~ OH 3.12 (1 H), ~ CH2 (vicinal to the ring) 2.75 ( 2 H, t, J = 7 Hz, ~ CH2 (C=O) 2.25 (2 H, t, J = 7 Hz), ~ CH2 1.95-1.1 (16 H, m), ~ CH3 0.9 (3 H, t, J = 5 Hz) ppm.
Mass spectrum : molecular weight 353.
Mass number of characteristic ions (m/e) : 353, 322, 282, 280, 254, 250, 238, 222~ 124.
Example 9 Preparation of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Ic, Rl = CH3) The solution of 47 mg of sodium borohydride in 10 ml of water was added to the solution of 912 mg of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, R1 = CH3) in 10 ml of isopropanol. The ob-tained reaction mixture was ~tirred for 2 hours ~t room temperature, then poured onto 50 ml water and extracted with 3 x 25 ml of ethyl acetate. ~he ethyl acetRte e~tract was washed with water until neutral, dried over sodium ~ulphate and evaporated under vacuum. The obtained 830 mg of residue on evaporation was purified by preparative thin layer chromatography, using a silicagel layer as adsorbent and a mixture of 50 ~ ethyl acetate and 50 X n-heptane as running solvent. Thus, 705 mg of 2-methyl-4-(6-carbo-methoxyhexyl)-5-(3-h;ydroxy-1-trans-octeng:l)-thiazole (Ic, R1 = CH3) of chromatographic purity were obtained.
IR spectrum (film~: ~ OH 3350, ~CH 3000-2860, ~ C=O 1740, ~ CaC 1640, ~ C-O 1255 cm 1.
NMR spectrum (CCl4): ~ CH~CH 6.48 (1 H, d, J ~ 15 Hz), 5.7 (1 H, dd, ~ ~ 15 Hz, J - 5.5 Hz), ~SC~(OH) 4.06 (1 H, m), ~ OCH3 3.56 (3H, 8)~ ~ OH 3.0 (1 H), ~ CH3 ~ ~CH2 (vicinal to the ring~ 2.55 (5 H), SCH2(C.O) 2.22 (2 H, t, J ~ 6~5 Hz), '~ S CH2 1.95-1.05 (16 H, m), SCH3 0.9 (3 ~, t, J - 5 Hz) ppm.
~ 20 Mas~ spe¢trum: molecular weight 367.
,~ ' 'Ma~ number of characteristic ions (m/e): 367, 336, 296, !~ 294~ 8, 264, ?52, 239, 236, 196, 183, 140.
Exam~le 10 ' Prèparation of 4-(6-oarboxyhexyl)-5-(3-hydroxy~
~25 trans-octenyl)-thiazole (Id, R1 Z H) ` ` To the suspensio~ of 1.75 g of 'l (6-carbomethoxyhexyl)-', 5-(3-hgdroxy-1-trans-octe~yl~-thiazole (Ic, R1 s H) in 35 ml of a 0.2 M ~hosphate buifer of p~ 7.5, 175 mg of the lipase en&yme ~pecified in Ex~mple 5, 17.5 mg of the aodiu~ salt of taurocholic acid o~d 1.75 ml of a 10 X solution of gum ' .~ ' , ' ' , . ' . , ' . . ' .

arabic were added. The mixture was then shaken at 25C in a screening shaker desk at 260 revolutions/mir,ute and an amplitude of 2 cm for 24 hours, whereafter the reaction mixture was diluted with 100 ml of water, acidified with citric acid and extracted with 3 x 70 ml of ethyl acetate.
The ethyl acetate extract was dried over sodium sulphate and evaporated under vacuum. The obtained 1.95 g of residue on evaporation was purified by chromatography on a column prepar-ed with 50 g of silicic acid, using as eluting agents mixtures of n-heptane and ethyl acetate whose ethyl acetate content was stepwise increased. 4-(6-Carbocyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole Id, R1 = H) was eluted from the column by a mixture consisting of 70 % ethyl acetate and 30 %
n-heptane. Thus, 1.25 g of a product of chromatographic purity was obtained which was recrystallized from a mixture of diethyl ether and n-hexane.
M.p. : 73-74C.
IR spectrum (film) : ~ OH 3500-2300, ~ CH 3000-2~60, ~ C=O 1710,~ C=C 1635 cm~l.
NMR spectrum (CDC13) : ~CH (thiazole) 8.55 (1 H s), OH 6.65 (2 H), ~ CH~CH 6.65 (1 H, d, J = 15 HZ), 5.9 ~1 H, dd, J = 15 HZ, J = 6 Hz), ~ CH(OH) 4.22 (1 H, m), ~ CH2 (vicinal to the ring) 2.75 (2 H, t, J = 6 Hz), 5 CH2(C=O) 2.28 (2 H, t, J = 6 Hz), ~ CH2 1.95-1.05 (16 H, m), ~ CH3 0,87 (3 H, t, J = 4 Hz) ppm.
Mass spectrum : molecular weight 339.
Mass number of characteristic ions (m/e) : 339, 321, 280, 268, 250, 240, 238, 225, 222, 182, 169, 152, 126, 124.
Example 11 Preparation of 2-methyl-4-(6-carboxyhexyl)-5-(3-hydro-xy-l-trans-octenyl)-thiazole (Id, Rl = CH3) The solution of 76 mg of sodium borohydride in 6 ml of water was added to the solution of 351 mg of 2-methyl-4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ib, Rl = CH3) in 4 ml of propanol. The reaction mixture was allowed to stand overnight at room temperature, then diluted with 50 ml of water, acidified with 1 N hydrochloric acid and extracted with 3 x 25 ml of ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated under vacuum. m e obtained 317 mg of residue on evaporation was purified by preparative thin layer chromato-lQ graphy in the way specified in Example 6. Thus, 245 mg of 2-methyl-4-(6-carboxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Id, Rl - CH3) were obtained.
IR speetrum (film) : OH 3500-2300, CH 3000-2860, C=O
1710, ~ C=C 1640 cm 1 NMR spectrum (CDC13) : ~ OH 7.15 (2 H), ~ CH=CH 6.55 (1 H, d, J = 15 Hz), 5.78 (1 H, dd, J = 15 Hz, J = 6 Hz), S CH(OH) 4.20 (1 H, m),~ CH3 + ~ CH2 (vieinal to the ring), 2.62 (5 H, m),~ CH2(C=O) 2.28 (2 H, t, J = 6 Hz), ~ CH2 1.9-1.05 (16 H, m), S CH3 0.9 (3 H, t, J = 5 Hz) ppm.
Mass speetrum : moleeular weight 353.
Mass number of eharaeteristic ions (m/e) : 353, 335, 294, 282, 264, 254, 252, 239, 236, 196, 183, 140.
Exam~Le 12 Preparation of 4-(6-carbomethoxyhexyl)-5-(3-aeetoxy--l-trans-oetenyl)-thiazole (Ie, Rl = H) To the solution of 353 mg of 4-(6-earbomethoxyhexyl)-5-(3-hydroxy-1-trans-oetenyl)-thiazole (Ie, Rl = H) in 4 ml of anhydrous pyridine, 1 ml of acetic anhydride was added.
The reaetion mixture was allowed to stand for 24 hours at room temperature, diluted with 50 ml of water and extraeted with 3 x 15 ml of ethyl aeetate. The ethyl aeetate extraet was washed with water, dried over sodium sulphate and .
, ~, , , , .. .. ,, .. , . . .: , . . .

evaporated under vacuum. The obtained 390 mg of residue on evaporation was purified by preparative thin layer chromato-graphy, using a silicagel layer as adsorbent and a mixture of 40 % ethyl acetate and 60 % n-heptane as running solvent.
Thus, 285 mg of 4-(6-carbomethoxyhexyl)-5-(3-acetoxy-1-trans-octenyl)-thiazole (Ie, Rl = H) of chromatographic purity were obtained.
IR spectrum (film) :~CH 3080, ~ CH 3000-2860, ~ C=O 1735, ~ C=C 1642, ~ C-O 1240 cm 1, NMR spectrum (CDC13) : ~ CH (thiazole) 8.46 (1 H, s), CH=CH 6.71 (1 H, d, J = 15 Hz), 5.76 (1 H, dd, J = 15 Hz, J = 6 Hz), S CH(OAc) 5.35 (1 H, m) ~ OCH3 3.6 (3 H, s), ~ CH2 (vicinal to the ring) 2.75 (2 H, t, J - 7 Hz), S CH2(C=O) 2.25 (2 H, t, J = 6 Hz), S CH3(C=O) 2.0 (3 H, s), ~ CH2 1.9-1.1 (16 H, m), 5 CH3 0.9 (3 H, t, J = S Hz) ppm.
Mass spectrum : molecular weight 395.
Mass number of characteristic ions (m/e) : 395, 353, 352, 336, 335, 324, 282,280, 267, 254, 250, 222.

Example 13 Preparation of 2-methyl-4-~6-carbomethoxyhexyl)-5-(3-acetoxy-1-trans-octenyl)-thiazole (Ie, Rl = CH3) To the solu~ion of 367 mg of 2-methyl-4-(6-carboxy-hexyl)-5-(3-hydroxy-1-trans-octenyl)thiazole (Ic, Rl = CH3) in 4 ml of anhydrous pyridine, 1 ml of acetic anhydride was added. The reaction mixture was allowed to stand for 24 hours at room temperature, diluted with 50 ml of water and extracted with 3 x 15 ml of ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulphate and evaporated under vacuum. The obtained 403 mg of residue on evaporation was purified by preparative thin layer chromatography, using a silicagel layer as adsorbent and a mixture of 40 % ethyl acetate and 60 % n-heptane as running solvent. Thus, 290 mg of 2-methyl-4-(6-carbomethoxy-hexyl)-5-(3-acetoxy-1-trans-octenyl)-thiazole (Ie, Rl = CH3 of chromatographic purity were obtained.

IR spectrum (film) : ~ CH 3000-2860,~ C=O 1735, ~ C=C 1640, l~c_o 1240 cm~l.
NMR spectrum ~CDC13) : ~ CH=CH 6.55 (1 H, d, J = 15 Hz), 5.60 (1 H, dd, J = 15 Hz, J = 6 Hz), ~CH(OAc) 5.3 (1 H, m), ~ OCH3 3~6 (3 H, s), ~ CH2 (vicinaI to ~he ring) 2.65 (2 H, t, J = 7 H~), ~ CH3 2.6 (3 H, s) ~ CH2(C=O) 2.3 (2 H, t, J = 7 Hz), ~ CH3(C=O) 2.05 (3 H, s) ~ CH2 1.9-1.05 (16 H, m), ~ CH3 0.9 (3 H, t, J = 5 Hz) ppm.
Mass spectrum : molecular weight 409.
Mass number of characteristic ions (m/e) : 409, 378, 367, 366, 350, 349, 338, 336, 296, 294, 281, 268, 238, N~/cooR2 R1-~S~ ' Rg (I) QEACTION SCHE~ 1 C~cocH2cooR4~ metal Na R500C (cH2 ) (Il) (111) R~sOOC (CH2)6CO-CH-COOR~
CzO
(Iv) CH3 --~H300C(CH~)6CO-CH2-COOCH~, --(~) --C~OOC(CH~)~,GO-CHY-COOCH3+Rl-C~ NH
(\/1 ) (Vll) lOS3683 ~_~VwCOOcH3 N_~VWCOOH

R~ ~5~ sl COOCH3 COOH + R20H
(VIII) (IX) N~/\/COOR2 ~ CR2 ' --R1~S,~ s ~
COOH COCl (x) (XI) N~/\/COOR2 N~/\~COOR2 --R~s,~ Rl~S~
~HaOH CHO
(Xll) (Xlll) N~\/COOR2 --R1~ ¦¦
S~w O
(1~) RfACT/0~/ SC~ lE2 C~OR2 r~OH
5~ S

O O
(la) (Ib) R~f~.CTlON SCHE/~lE 3 COOR2 N~COOR2 R~S ; ~ R

OH
(la) ( Ic) I~EACTION SCHE~E 4 R~ R1~r~
S S~
0~

(Ib) (Id) ~2 "~}
. ~
: :
.

R~ l~/COOR2 y~ COOH

S~W S~W
OH OH
(Ic) (Id) R~ACTION SCHE11f 6 R1~ ~/GOOR N~COOR2 5~ ~ S~ ' ``
OH
(IC) ( le)

Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the production of thiazole derivatives of the general formula I
(I) wherein R1 and R2 stand for hydrogen atoms or alkyl groups, and R3 stands for an oxo, hydroxyl or acyloxy group, comprising the steps of a) acylating the sodium derivative of an acetoacetic acid alkylester of the formula CH3COCH2COOR4, wherein R4 denotes an alkyl group, with a 7-carbalkoxyheptanoyl chloride of the formula R5OOC(CH2)6COCl, wherein R5 denotes an alkyl group, and converting the obtained 10-carbalkoxy-2,4-diketodecane-3-carboxylic acid alkylester of the formula , wherein R4 and R5 have the same meanings as above, with sodium methylate into 9-carbomethoxy-3-ketononanic acid methylester of formula CH3OOC(CH2)6CO-CH2-COOCH3 , halogenating the latter compound to 9-carbomethoxy-2-halo-3-ketononanic acid methylester of the formula CH3OOC(CH2)6CO-CHY-COOCH3 , wherein Y denotes a halogen atom, reacting the last-named compound with a thioacid amide of the formula , wherein R1 denotes a hydrogen atom or an alkyl group, hydrolyzing the obtained 4-(6-carbo-methoxyhexyl)-thiazole-5-carboxylic acid methylester of the formula wherein R1 stands for a hydrogen atom or an alkyl group, to obtain 4-(6-carboxyhexyl)-thiazole-5-carboxylic acid of the formula wherein R1 is a hydrogen atom or an alkyl group, subjecting the last-named compound to selective esterification with an alcohol of the general formula R2OH, wherein R2 stands for an alkyl group, in the presence of p-toluenesulphonic acid, converting the thus-obtained 4-(6-carbalkoxyhexyl)-thiazole-5-carboxylic acid of the formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, into 4-(6-carbalkoxyhexyl)-thiazole-5-carboxylic chloride of the general formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, reducing the last-named compound with an alkali metal borohydride to 4-(6-carbalkoxyhexyl)-5-hydroxy-methyl-thiazole of the formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, then oxidizing the last-named compound to 4-(6-carb-alkoxyhexyl)-thiazole-5-carbaldehyde of the formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, reacting the last-named compound with 2-oxo-heptylidene-triphenyl phosphorane to obtain 4-(6-carbalkoxyhexyl)-5-(3-keto-1-trans-octenyl)- thiazole of the formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, or, b) reducing 4-(6-carbalkoxyhexyl)-thiazole-5-carboxylic chloride of the formula wherein R1 stands for a hydrogen atom or an alkyl group and R2 stands for an alkyl group, with lithium tri-tert.-butoxy-aluminium hydride to 4-(6-carbalkoxyhexyl)-thiazole-5-carbaldehyde of the formula wherein R1 stands for a hydrogen atom or an alkyl group and R2 stands for an alkyl group, then reacting the last-named compound with 2-oxo-heptylidene-triphenyl phosphorane to obtain 4-(6-carb-alkoxyhexyl)-5-(3-keto-1- trans-octenyl)-thiazole of the formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, or, c) reacting 4-(6-carbalkoxyhexyl)-thiazole-5-carbaldehyde of the formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, with the sodium derivative of 2-oxo-heptyl-phosphonic acid dimethylester or with 2-oxo-haptylidene-triphenyl phosphorane into 4-(6-carbalkoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole of the formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, and, if desired, hydrolyzing the last-named compound to 4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole of the formula wherein R1 is a hydrogen atom or an alkyl group, or, if desired, reducing 4-(6-carbalkoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole of the above formula with an alkali metal borohydride to 4-(6-carbalkoxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole of the formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, or, if desired, reducing 4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole with an alkali metal borohydride, or hydrolyzing 4-(6-carb-alkoxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole of the above formula to 4-(6-carboxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole of the formula wherein R1 stands for a hydrogen atom or an alkyl group, or acylating 4-(6-carbalkoxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole of the above formula to 4-(6-carbalkoxyhexyl-5-(3-acyloxy-1-trans-octenyl)-thiazole of the formula wherein R1 stands for a hydrogen atom or an alkyl group and R2 stands for an alkyl group.

2. A process as claimed in claim 1 , characterized by carrying out the chlorination of 9-carbomethoxy-3-ketononanic acid methylester with sulphuryl chloride.

3. A process as claimed in claim 1, characterized by carrying out the hydrolysis of 4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester of the formula wherein R1 is a hydrogen atom or an alkyl group, with an alkali hydroxide.

4. A process as claimed in claim 1, characterized by carrying out the oxidation of 4-(6-carbalkoxyhexyl)-5-hydroxymethylthiazole of the formula wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, with a chromium trioxide-dipyridine complex.

5. A process as claimed in claim 1, characterized by carrying out the hydrolysis of the ester group of the compounds of the formula and respectively, wherein R1 is a hydrogen atom or an alkyl group and R2 is an alkyl group, with an esterase enzyme.

6. New thiazole derivatives of the general formula I

(I) wherein R1 and R2 stand for hydrogen atoms or alkyl groups, and R3 stands for an oxo, hydroxyl or acyloxy group, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.