CH634062A5 - Process for preparing substituted thiazolidinecarboxylic, oxazanecarboxylic and thiazanecarboxylic acids and their esters - Google Patents

Description

50 The invention relates to the production of new substituted thiazolidine, oxazane, thiazane and related carboxylic acids, and their esters, of the general formula I.

55

X

/ \

(R2-CH) ra (CH-Ri) n

(I)

r3

I.

«0 R4-S- (CHz) p-CH-CO - N-

*

-CH-CO-R

*

in which R represents a hydroxyl group or a lower alkoxy radical, R 1 and R 2 each represent hydrogen atoms or lower alkyl radicals, R 3 represents a hydrogen atom, a lower alkyl or mercapto-lower alkyl radical, R 4 represents a hydrogen atom, a benzoyl group, a lower alkanoyl radical or the rest

x

* /

Ri (R.2-CH) m (CH-Rl) n

I I I

-S- (CH:) p-CH-CO - N CH CO-R

* *

X represents an oxygen or sulfur atom or a sulfinyl or sulfonyl group, m the value 1, 2 or 3, n the value 0, 1 or 2, (m + n) the value 2 or 3 and p the value Have 0 or 1, with the proviso that m has the value 2 and n has the value 1 when X represents an oxygen atom, and their salts and derivatives.

In the formula (I) asymmetry centers are marked with an asterisk.

The compounds according to the invention are characterized by an unsubstituted or lower-alkyl-substituted 5- or O-membered heterocyclic carboxylic acid with one nitrogen atom and one sulfur or oxygen atom in the ring, the other ring atoms being carbon atoms. Thiazolidinic, thiazanic and morpholinecarboxylic acids are preferred. In addition to the nitrogen atom, the ring contains a further heteroatom, namely an oxygen or sulfur atom, the sulfur atom being the

Sulfinyl group (-S-) or sulfonyl group (-S-)

can be oxidized. The side chain attached to the nitrogen atom of the heterocycle is a substituted or unsubstituted mercaptoalkanoyl group. The compound can also be in a “dimeric” form, in which the sulfur-containing substituted radical R4 represents a similar unit.

The lower alkyl residues include straight chain or branched hydrocarbon residues from methyl to heptyl, e.g. the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and isopentyl group. The lower alkyl residues are of the same type and contain 1 to 7 carbon atoms. The alkoxy radicals are also of the same type with an oxygen bond, examples are the meth-oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy group. Among the radicals mentioned, radicals having 1 to 4 carbon atoms are preferred and radicals having 1 or 2 carbon atoms are particularly preferred. The lower alkanoyl residues are the acyl residues of lower (up to 7 carbon atoms) fatty acids, such as the acetyl, propionyl and butyryl group, with the acetyl group being preferred.

In preferred compounds of the formula (I) R is a hydroxyl group or a lower alkoxy radical, in particular a hydroxyl, methoxy or ethoxy group, R 1 and R 2 are hydrogen atoms or lower alkyl radicals, preferably hydrogen atoms, methyl or ethyl groups and in particular hydrogen atoms, R 3 is a hydrogen atom, a lower alkyl radical, in particular a methyl or ethyl group, or a mercapto-lower alkylene radical, in particular a mercaptomethyl group, R4 is a hydrogen atom, a lower alkanoyl radical, in particular an acetyl group or a benzoyl group, and X is a sulfur or oxygen atom, in particular a sulfur atom, while m has the value 1 or 2, n the value 1 and p the value 0 or 1, in particular the value 1.

The compounds of formula (I) in which R4 represents a hydrogen atom, a benzoyl group or a lower alkanoyl radical are obtained by acylation of an acid of the general formula II

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X

(r2-CH) m (CH-Rl) n (II)

I I

HN CH - CO-R

in which R is a hydroxyl group and the other radicals have the above meaning, with an acid of the general formula III R3

I.

R4-S- (CH2) p-CH-COOH (III)

prepared, preferably by one of the known methods, in which the acid (III) is activated before the reaction with the acid (II), e.g. to form a mixed anhydride, symmetrical anhydride, acid chloride,

active ester, Woodward's reagent K, N, N'-carbonylbisimidazole or N-ethoxycarbonyl-2-ethoxy-l, 2-dihydrochi-nolins. If R is a lower alkoxy radical, this method or other known methods for coupling such groups can be used. An overview of such processes can be found in "Methods of Organic Chemistry" (Houben-Weyl), Vol. XV, Parts 1 and 2 (1974).

The acid (II) can also be acylated in stages. For example, a fragment of the acylating agent (III) can first be bound to the acid (II) by e.g. with a haloacyl halide of the general formula (purple)

Rs hal- (CH:) p-CH-CO-hal (purple)

is a halogen atom, preferably a chlorine or bromine atom, such as 3-bromopropionyl chloride. This creates a compound of the formula (Illb)

X

R3 (R2-CH) m (CH-Ri) n (Illb)

I I I

hal- (ch2) P-CH-CO N CH-CO-R

The desired product (I) is then obtained by reacting this intermediate with a thiol: R4-SH. This stepwise acylation is explained in the examples.

If the product is obtained as an ester, i.e. if R is a lower alkoxy radical, the ester can be converted into the free carboxylic acid by alkaline hydrolysis or by treatment with trifluoroacetic acid and anisole. Conversely, the free acid can be esterified in the usual way.

Disulfides of the general formula I in which R4 is the rest:

X

/ \ R3 r2-CH (CH-Ri) m

I I I

-S- (CH2) p-CH-CO - N CH -CO-R

is, by oxidation of a compound of formula IV

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X

Rî (R2-CH) m (CH-Rl) m

I I I

HS- (CH2) p-CH-CO N CH-CO-R (IV)

e.g. obtained with an alcoholic iodine solution.

The compounds (I) have at least 1 and up to 4 asymmetric carbon atoms. These carbon atoms are marked with an asterisk in formula (I). Accordingly, the compounds are in the form of diastereoisomers or corresponding racemic mixtures, all of which are the subject of the invention. Both the racemates and the enantiomers can be used as starting materials in the synthetic processes described above. If a racemic starting material is used, the stereoisomers obtained can be separated in a conventional manner, e.g. by chromatography or fractional crystallization. In general, the L isomer is the preferred isomer with respect to the carbon atom of the amino acid.

The compounds produced according to the invention form basic salts with various organic and inorganic bases. Examples of such salts are ammonium salts, alkali metal salts, preferably sodium and potassium salts, alkaline earth metal salts, e.g. Calcium and magnesium salts, salts with organic bases such as dicyclohexylamine, benzathine, N-methyl-D-glucamine and hydrabamine, and salts with amino acids such as arginine and lysine. The non-toxic, physiologically acceptable salts are preferred, although other salts can also be used, e.g. to isolate or clean the product as in the case of the dicyclo-hexylamine salt.

The salts are prepared in a conventional manner by reacting the free acid with one or more equivalents of a suitable base which provides the desired cation in a solvent or medium in which the salt is insoluble, and filtering or reacting in water and the water removed by freeze drying. By neutralizing the salt with an insoluble acid, e.g. a cation exchange resin in the H form - (for example a polystyrene sulfonic acid resin: Dowex 50 [Mikes, Laboratory Handbook of Chromatographie Methods, Van Nostrand (1961), p. 256]} or with an aqueous acid and extraction with an organic solvent such as ethyl acetate or Dichloromethane, the free acid is obtained and this can optionally be converted into another salt.

The compounds produced according to the invention inhibit the conversion of the decapeptide angiotensin I to angiotensin II and are therefore suitable for reducing or eliminating angiotensin-induced hypertension. Angiotensin I is caused by the action of the enzyme renin on angiotensinogen, a pseudoglobulin in the blood plasma. Angiotensin I is converted to angiotensin II by the angiotensin converting enzyme ACE. The latter is an active pressure-increasing substance that is considered to be the cause of various forms of hypertension in mammals, such as rats and dogs. The compounds according to the invention intervene in the angiotensinogen-angiotensin I-angiosensin Ii sequence by inhibiting the angiotensin converting enzyme and reducing or preventing the formation of the pressure-increasing substance angiotensin II.

The inhibition of the angiotensin converting enzyme by the compounds (I) can be measured in vitro with angiotensin converting enzyme isolated from rabbit lungs; see. Cushman and Cheung [Biochem. Pharmacol., Vol. 20, p. 1637 (1971)]. A test with prepared smooth muscles can also be used [E. O'Keefe et al., Federation Proc. Vol. 31, p. 511 (1972)], in which the compounds prove to be effective inhibitors of the contracting action of angiotensin I and as potentiators of the contracting activity of bradykinin.

By administering a drug containing one or more compounds (I) or a corresponding physiologically acceptable salt to hypertonic mammals, a reduction or elimination of the angiosensin-dependent hypertension is achieved. Single doses or preferably 2 to 4 divided daily doses based on about 5 to 1000 mg / lcg and day, preferably about 10 to 500 mg / kg and day, are suitable for lowering the blood pressure. The animal model experiments by S. L. Engel, T. R. Schaeffer, M. H. Waugh and B. Rubin, Proc. Soc. Exp. Biol. Med. Vol. 143, p. 483 (1973) give suitable guidelines.

The drugs are preferably administered orally, but other types of administration, e.g. subcutaneously, intramuscularly, intravenously or intraperitoneally.

The drugs of the invention can e.g. be formulated as tablets, capsules or elixirs for oral administration or as sterile solutions or suspensions for parenteral administration. For this purpose, about 10 to 500 mg of one or more compounds (I) or a physiologically tolerable salt are processed in customary manner with physiologically tolerable carriers, binders, excipients, preservatives, stabilizers, taste correctors and / or other auxiliaries to form dosage units. If necessary, the medicinal products may contain other active substances. The active ingredient concentration of the medicinal products is selected so that a suitable dosage in the above range is achieved.

The examples illustrate the invention.

example 1

3- (3-Benzoylthiopropanoyl) -4-L-thiazolidinecarboxylic acid

A solution of 6.6 g of L-4-thiazolidinecarboxylic acid in 50 ml of 1N sodium hydroxide solution, cooled in an ice bath, is successively mixed with 25 ml of 2N sodium hydroxide solution and 8.5 g of 3-bromopropionyl chloride with vigorous stirring. After 3 hours, a suspension of 7.5 g of thiobenzoic acid and 4.8 g of potassium carbonate in 50 ml of water is added, the reaction mixture is stirred at room temperature overnight and filtered. The filtrate is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and evaporated to dryness, whereupon the residue is chromatographed on silica gel with benzene / acetic acid (7: 1) and the purified material is crystallized from ethyl acetate / ether / hexane. This gives the desired compound, mp 105 to 106 ° C.

The product is dissolved in water and mixed with an equivalent amount of sodium hydroxide solution. The sodium salt is obtained by freeze-drying the solution.

Example 2

3- (3- (Mercaptopropanoyl) -L-4-thiazolidinecarboxylic acid

6.7 g of 3- (3-benzoylthiopropanoyl) -L-4-thiazolidinecarboxylic acid are dissolved under argon protection in a mixture of 15 ml of water and 7.5 ml of concentrated ammonia. After storage for one hour at room temperature, the reaction mixture is diluted with 20 ml of water and filtered. The filtrate is extracted with ethyl acetate, acidified with concentrated hydrochloric acid and extracted again with ethyl acetate. The second ethyl acetate extract is dried and dried

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no evaporated. Crystallization of the residue from ethyl acetate gives the desired compound, mp 110 to 112 ° C.

Example 3

3-acetylthio-2-methylpropionic acid s

A mixture of 50 g of thioacetic acid and 40.7 g of methacrylic acid is heated on a steam bath for 1 hour and then left to stand at room temperature for 18 hours. Then the reaction mixture is distilled under reduced pressure and the fraction is collected with a bp. 2.6 Torr of 10 128.5 to 131 ° C.

The desired compound can also be isolated by letting the reaction mixture crystallize after dilution with hexane, mp 40 to 42 ° C.

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Example 4

Methyl 3- (3-acetylthio-2-methylpropanoyl) -2-thiazolidinecarbonate

4.4 g of 2-thiazolidinecarboxylic acid methyl ester (C.A. Vol. 53, 12 281 d) and 4.0 g of 3-hydroxybenzotriazole are dissolved in 40 ml of 2o dichloromethane, whereupon the solution is stirred and cooled in an ice bath. A solution of 6.2 g of dicyclohexylcarbodiimide in 15 ml of dichloromethane is then added, followed immediately by a solution of 4.9 g of 3-acetyl-2-methyl-propionic acid in 5 ml of dichloromethane. Stir 15 25

Minutes in an ice bath and 16 hours at room temperature, then the precipitate is filtered off and the filtrate is washed until neutral. The desired compound is obtained by drying and evaporating the organic layer under reduced pressure. 30th

Example 5

3- (3-Mercapto-2-methylpropanoyI) -2-thiazoIidine carboxylic acid

2.9 g of 3- (3-acetylthio-2-methylpropanoyl) -2-thiazolidine-35 carboxylic acid methyl ester are dissolved in 30 ml of methanol and mixed with 30 ml of 1N sodium hydroxide solution. The reaction mixture is stirred at room temperature, equal amounts being drawn off every hour and checked for the hydrolysis of the methyl ester by paper electrophoresis. After complete hydrolysis (about 3 hours), the reaction mixture is neutralized, evaporated under reduced pressure to separate the methanol, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The desired compound is obtained by drying and evaporating the organic layer.

Example 6

3- (3-acetylthio-2-methylpropanoyl) -2-ethyl-4-thiazolidinecarboxylic acid 50

A 5.2 g solution chilled in an ice / water bath

2-ethyl-4-thiazolidinecarboxylic acid [Z. Naturforschung, vol. 17b, p. 765 (1962)] in 30 ml of 1N sodium hydroxide solution is mixed with 5.4 g

3-acetylthio-2-methylpropionic acid chloride (prepared from 3-acetylthio-2-methylpropionic acid and thionyl chloride; 55 bp. 80 ° C.) and 15 ml of 2N sodium hydroxide solution. After stirring for three hours at room temperature, the mixture is extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The desired compound is obtained by drying the organic phase over magnesium sulfate and evaporating under reduced 6o pressure.

Example 7

2-ethyl-3- (3-mercapto-2-methylpropanoyl) -4-thiazolidine carboxylic acid 05

1 g of 3- (3-acetylthio-2-methylpropanoyl) -2-ethyl-4-thiazolinedicarboxylic acid is dissolved under argon protection in a mixture of 3 ml of water and 3 ml of concentrated ammonia.

The mixture is stirred for 30 minutes at room temperature and acidified with concentrated hydrochloric acid. The desired compound is obtained by drying the organic layer and evaporating under reduced pressure.

Example 8

3- (3-mercapto-2-methylpropanoyl) -5-methyl-4-thiazolinedicarboxylic acid

Using 5-methyl-4-thiazolidine carboxylic acid [Org. Mag. Resonance, Vol. 6, p. 48 (1974)] instead of ethyl 4-thiazolidinecarboxylic acid in the process of Example 6 and further processing of the product according to Example 7, 3- (acetylthio-2-methylpropanoyl) -5-methyl- 4-thiazolidine carboxylic acid and 3- (3-mercapto-2-methylpropanoyl) -5-methyl-4-thiazolidine carboxylic acid.

Example 9

3 - [(2-acetylthiomethyl) -3-acetylthiopropanoyl] -4-L-thiazolidinecarboxylic acid

A solution of 1.66 g of 4-L-thiazolidine carboxylic acid and 2.7 g of sodium carbonate in 25 ml of water is cooled in an ice bath and mixed with 3.9 g of 2- (acetylthiomethyl) -3-acetylthiopropionic acid chloride [prepared from 2- ( Acetylthiomethyl) -3-ace-tylthiopropionic acid and thionyl chloride] were added, whereupon the mixture was stirred vigorously at room temperature for 2 hours. After extraction with ethyl acetate, the aqueous layer is acidified and extracted with ethyl acetate. The desired compound is obtained by drying the organic layer and evaporating to dryness.

Example 10

3 - [(2-mercaptomethyl) -3-mercaptopropanoyl] -4-L-thiazo-lidoic acid

Using 3 - [(2-acetylthiomethyl) -3-acetylthiopropanoyl] -4-L-thiazolidinecarboxylic acid instead of 3- (3-acetylthio-2-methylpropanoyl) -2-ethyl-4-thiazolidine-carbonic acid im Following the procedure of Example 7, the desired compound is made.

Example 11

3- (3-mercaptopropanoyl) -1,3-thiazane-4-carboxylic acid

Using 1,3-thiazane-4-carboxylic acid [J. Biol. Chem., P. 607 (1957)] instead of 4-L-thiazolidinecarboxylic acid in the process of Example 1 and further processing of the product according to Example 2, 3- (3-benzoylthiopropanoyl) -1,3-thiazan-4 -carboxylic acid and 3- (3-mercaptopropanoyl) -1,3-thiazane-4-carboxylic acid.

Example 12

3- (3-Mercapto-2-methylpropanoyl) -1, 3-thiazane-4-carboxylic acid

Using 1,3-thiazane-4-carboxylic acid instead of 2-ethyl-4-thiazolidinecarboxylic acid in the process of Example 6 and further processing of the product according to Example 7, 3- (3-acetylthio-2-methylpropanoyl) -l, 3rd -Thiazan-4-carboxylic acid and 3- (3-mercapto-2-methylpropa-noyl) -1,3-thiazan-4-carboxylic acid.

Example 13

3 - [(2-mercaptorethyl) -3-mercaptopropanoyl] -1,3-thiazane-4-carboxylic acid

Using 1,3-thiazane-4-carboxylic acid instead of 4-thiazolidinecarboxylic acid in the process of Example 9 and further processing of the product according to Example 7, 3 - [(2-acetylthiomethyl) -3-acetylthiopropa-noyl] -l, 3 -thiazane-4-carboxylic acid and 3 - [(2-mercaptomethyl) -3-mercaptopropanoyl] -1,3-thiazane-4-carboxylic acid.

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Example 14

4- (3-acetylthiopropanoyl) -3-methyl-l, 4-thiazane-5-carboxylic acid

8.3 g of 3-acetylthiopropanoyl chloride are added to a mixture of 8 g of 3-methyl-1,4-thiazane-5-carboxylic acid [Acta. Chem. Scand., Vol. 13, p. 623 (1959)] in dimethylacetamide, the temperature being kept below 25.degree. 10.1 g of N-methylmorpholine are then added and the mixture is heated on a steam bath for 1 hour. After cooling to room temperature, the precipitate formed is filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with 1% potassium bisulfate solution. The desired compound is obtained by drying the organic layer and evaporating to dryness.

Example 15

4- (3-mercaptopropanoyl) -3-methyl-l, 4-thiazane-5-carboxylic acid

Using 4- (3-acetylthiopropanoyl) -3-methyl-1,4-thiazane-5-carboxylic acid instead of 3- (3-acetylthio-2-methyl-propanoyl) -2-ethyl-4-thiazolidinecarboxylic acid in Method of Example 7, the desired compound is made.

Example 16

4- (3-mercapto-2-methylpropanoyl) -3-methyl-1,4-thiazane-5-carboxylic acid

Using 3-acetylthio-2-methylpropa-noyl chloride instead of 3-acetylthiopropanoyl chloride in the process of Example 14 and further processing of the product according to Example 7, 4- (3-acetylthio-2-methylpro-panoyl) -3-methyl-1 , 4-thiazane-5-carboxylic acid and 4- (3-mer-capto-2-methyl-propanoyl) -3-methyl-1,4-thiazane-5-carboxylic acid.

Example 17

4 - [(2-mercaptomethyl) -3-mercaptopropanoyl] -3-methyl-1,4-thiazane-5-carboxylic acid

Using 2- (acetylthiomethyl) -3-acetylthio-propionic acid chloride instead of 3-acetylthiopropanoyl chloride in the process of Example 14 and further processing of the product according to Example 7, 4 - [(2-acetylthio-methyl) -3- (acetylthio ) -propanoyl] -3-methyl-1,4-thiazane-5-carboxylic acid and 4 - [(2-mercaptomethyl) -3-mercaptopropa-noyl] -3-methyl-1,4-thiazane-5-carboxylic acid.

Example 18

4- (3-mercapto-2-methylpropanoyl) -l-oxo-1,4-L-thiazane-5-carboxylic acid

Using 3-acetylthio-2-methylpropa-noyl chloride instead of 3-acetylthiopropanoyl chloride and l-oxo-1,4-thiazane-5-carboxylic acid (CA, Vol. 55.95801) instead of 3-methyl-1,4 -thiazane-5-carboxylic acid in the process of Example 14 and further processing of the end product according to Example 7 are 4- (3-acetylthio-2-methylpro-panoyl) -1-oxo-1,4-L-thiazane-5-carboxylic acid and 4- (3-Mer-capto-2-methylpropanoyl) -1-oxo-1,4-L-thiazane-5-carboxylic acid.

Example 19

4 - [(3-Acetylthio) -2-methylpropanoyl] -1,4-thiazan-3-carboxylic acid ethyl ester

Using 1,4-thiazane-3-carboxylic acid ethyl ester [J. Chem. Soc., P. 203 (1976)] instead of methyl 2-thiazolidinecarboxylate in the process of Example 4, the desired compound is prepared.

Example 20

4- (3-mercapto-2-methylpropanoyl) -1,4-thiazane-3-carboxylic acid

Using 4 - [(3-acetylthio) -2-methylpropa-noyl] -l, 4-thiazane-3-carboxylic acid ethyl ester instead of 3- (3-acetylthio-2-methylpropanoyl) -2-thiazolidinecarboxylic acid methyl ester in the process of Example 5 produces the desired compound.

Example 21

N - [(2-acetylthiomethyl) -3- (acetylthio) propanoyl] -3-morpholine carboxylic acid

Using 3-morpholine carboxylic acid instead of 4-thiazolidine carboxylic acid in the procedure of Example 9, the desired compound is prepared.

Example 22

N - [(2-mercaptomethyl) -3-mercaptopropanoyl] -3-morpho-linocarboxylic acid

Using N - [(2-acetylthiomethyl) -3- (acetylthio) propanoyl] -3-morpholine carboxylic acid instead of 3 - [(2-acetylthiomethyl) -3- (acetylthio) propanoyl] -4-L- thiazolidine carboxylic acid in the process of Example 10, the desired compound is prepared.

Example 23

3- (2-Benzoylthiopropanoyl) -4-L-thiazolidinecarboxylic acid

Using 2-bromopropionyl chloride instead of 3-bromopropionyl chloride in the procedure of Example 1, the desired compound is prepared.

Example 24

3- (2-mercaptopropanoyl) -4-L-thiazolidinecarboxylic acid

Using 3- (2-benzoylthiopropanoyl) -4-L-thiazolidinecarboxylic acid instead of 3- (3-benzoylthiopropa-noyl) -4-L-thiazolidinecarboxylic acid in the procedure of Example 2, the desired compound is prepared.

Example 25

3,3 '- [Dithio-bis- (3-propanoyl)] - bis-L-thiazolidine-4-car-bonic acid

An alcoholic iodine solution is added to an equimolar aqueous mixture of 3- (3-mercaptopropanoyl) -L-thiazo-lidin-4-carboxylic acid until a permanent yellow color develops, the pH being adjusted between 5 and 7 by carefully adding 1N sodium hydroxide solution holds. The yellow color is then removed with a few drops of sodium thiosulfate, whereupon the mixture is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The desired compound is obtained by drying the organic layer and evaporating under reduced pressure.

Example 26

1, l-dioxo-3-methyl-1,4-thiazane-5-carboxylic acid

A solution of 6 g of 3-methyl-1,4-thiazane-5-carboxylic acid in 300 ml of acetic acid is stirred at 45 ° C. for 6 hours, 25 ml of 30 percent hydrogen peroxide being added at a rate of 5 ml / hour. admits. The desired compound is obtained by allowing the solution to stand overnight and removing the solvent under reduced pressure.

Example 27

l, l-Dioxo-4- (3-mercapto-2-methylpropanoyl) -3-methyl-1,4-thiazane-5-carboxylic acid

Using 1,1-dioxo-3-methyl-1,4-thiazane-5-carboxylic acid instead of 3-methyl-1,4-thiazane-5-carboxylic acid in the process of Example 16 and further processing see

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of the product according to Example 7, l, l-dioxo-4- (3-acety-lthio-2-methylpropanoyl) -3-methyl-1,4-thiazan-5-carboxylic acid and l, l-dioxo-4- (3-mercapto-2-methylpropanoyl) -3-methyl-1,4-thiazane-5-carboxylic acid.

Example 28

3- (3-Mercapto-2-methylpropanoyl) -L-4-thiazolidincarbonic acid

Using L-4-thiazolidinecarboxylic acid instead of 2-ethyl-4-thiazolidinecarboxylic acid in the process of Example 6 and further processing of the product according to Example 7, the 3- (3-acetylthio-2-methylpropanoyl) -L-4-thiazolidinecarboxylic acid ( Dicyclohexylammonium salt, crystallized from acetonitrile, sinters at 130 ° C and melts at 172-I88 ° C)

and 3- (3-mercapto-2-methylpropanoyl) -L-4-thiazolidinecarboxylic acid (dicyclohexylammonium salt, crystallized from ethyl acetate-hexane, sintered at 170 ° C and melts at 180-188 ° C).

Example 29

3,3 '- [dithio-bis- (2-methyl-3-propanoyl)] - bis-thiazolidine-2-carboxylic acid

Using 3- (3-mercapto-2-methylpropanoyI) thiazolidine-2-carboxylic acid instead of 3- (3-mercaptopropa-noyl) -L-thiazolidine-4-carboxylic acid in the procedure of Example 25, the desired compound is prepared.

Example 30

4- (3-Acetylthiopropanoyl) -Ll, 4-thiazan-5-carboxylic acid 6.6 g (0.036 mol) L-4-thiomorpholine-3-carboxylic acid hydrochloride are dissolved in 150 ml dimethylacetamide and mixed with 5.97 g (0.036 Mol) 3-acetylthiopropanoyl chloride added. The temperature rises to 28 ° C. 10.9 g (0.108 mol) of N-methylmorphopholine are then added to the solution, the temperature rising to 42 ° C. and a white precipitate forming immediately. The mixture is heated on a steam bath for 1 hour and then left overnight at room temperature. When filtering the

Solid is obtained 9.7 g of 4- (3-acetylthiopropanoyl) -L-l, 4-thiazan-5-carboxylic acid, mp 202 to 204 ° C. Removing the solvent gives a viscous residue, which is digested with water and 20 percent hydrochloric acid. The separated oil is extracted three times with 150 ml of ethyl acetate, whereupon the extracts are dried over magnesium sulfate, the solvent is separated off and the viscous residue (7.5 g) is left to crystallize. After recrystallization from acetone / hexane, the product melts constantly at 122 to 125 ° C.

Example 31

4- (3-Mercaptopropanoyl) -L-1,4-thiazane-5-carboxylic acid Aqueous ammonia (13 ml concentrated ammonium is hydroxide in 30 ml water) is stirred under nitrogen for 15 minutes and mixed with 6.8 g (0.024 mol) solid 4- (3-acetylthiopro-panoyl) -Ll, 4-thiazane-5-carboxylic acid added. At 5 to 10 ° C, a clear solution is formed immediately, under nitrogen

Is stirred for 1 hour at room temperature. The solution is then extracted with 100 ml of ethyl acetate and the aqueous layer is strongly acidified with 20 percent hydrochloric acid. The separated oil is extracted three times with 150 ml of ethyl acetate, whereupon the extracts are combined and dried over magnesium sulfate. By removing the solvent, 5.6 g of a semicrystalline mass are obtained, which apparently contains significant amounts of the starting material. The separated material (5.6 g) becomes even more

Hydrolyzed for 2 hours with 12 ml of concentrated ammonium hydroxide in 25 ml of water. The solution obtained is applied

30 acidifies and the separated oil is extracted three times with 150 ml of ethyl acetate. The extracts are combined and dried over magnesium sulfate. When the solvent is separated off, 2.7 g (48%) of the desired compound are obtained as a viscous mass after drying overnight at room temperature and a pressure of 1 torr.

Elemental analysis for C8H13NO3S2:

Calc .: N 5.95 40 Found: N 6.13

C 40.82 C 40.85

H 5.56 S 27.25 H 5.46 S 27.38

SH 100% SH 96%

B

Claims (9)

634 062 2. The method according to claim 1, in which R is a hydroxyl group or a lower alkoxy radical, R 1 and r 2 are each hydrogen atoms or lower alkyl radicals, R 3 is a hydrogen atom, a lower alkyl or mercapto-lower alkyl radical and X is a sulfur or oxygen atom and m has the value 1 or 2, n has the value 1 and p has the value 0 or 1. 2nd PATENT CLAIMS 1. Process for the preparation of the new compounds of general formula I X (CH-Rl) n (I) I. -CH-CO-R rj (r2-CH) ir I I R4-S- (CH2) p-CH-CO N- in which R represents a hydroxyl group or a lower alkoxy radical, R 1 and r 2 represent hydrogen atoms or lower alkyl radicals, R3 represents a hydrogen atom, a lower alkyl or mercapto-lower alkyl radical, R4 represents a hydrogen atom, a benzoyl group or a lower alkanoyl radical X represents an oxygen or sulfur atom or a sulfinyl or sulfonyl group, m the value 1, 2 or 3, n the value 0.1 or 2, (m + n) the value 2 or 3 and p the value 0 or 1, with the proviso that m is 2 and n is 1 when X is an oxygen atom, and their salts, characterized in that a compound of general formula II X (R: -CH) " I. HN— (CH-Rl) n I. -CH COR (ii) in which R, Ri, r2, X, m and n have the meaning given above, with a compound of the general formula III Rs Y- (CH2) p-CH-COOH (III) 10. The method of claim 1, wherein X represents a sulfur atom. 11. The method according to claim 10, in which R is a hydroxyl group, Ri, r2 and R3 are hydrogen atoms and R4 is a ben- 3. The method according to claim 1, in which R is a hydroxyl, methoxy or ethoxy group, R 1, R 2 and R 3 are hydrogen atoms, methyl or ethyl groups, R 4 is a hydrogen atom, an acetyl or benzoyl group and X is a sulfur atom and m is 1 or 2, n has the value 1 and p has the value 0 or 1. 4. The method of claim 1, wherein R4 represents a hydrogen atom. 5. The method according to claim 1, in which R4 denotes an acetyl group. 5 mean zoyl group and m, n and p have the value 1. 12. The method of claim 10, wherein R is a hydroxyl group and Ri, r2; R3 and R4 denote hydrogen atoms and m, n and p have the value 1. 13. The method of claim 10, wherein R is a hydroxyl 10 group, Ri, r2 and R4 are hydrogen atoms and R3 is a methyl group and m, n and p have the value 1. 14. The method according to claim 10, in which R is a hydroxyl group, Ri, r2 and R3 are hydrogen atoms and R4 is an acetyl group and m is 2, n is 1 and p is 15 "have value 1. 15. The method according to claim 10, in which R is a hydroxyl group and R 1, r 2, R 3 and R 4 are hydrogen atoms and m is 2, n is 1 and p is 1. 16. The method according to claim 1, characterized in 20 that a resulting ester of the formula I in which R is a lower alkoxy radical is saponified to give the corresponding acid of the formula I in which R is a hydroxyl group. 17. The method according to claim 1, characterized in that an acid of the formula I obtained, in which R is a 25 hydroxyl group is esterified to a compound of the formula I in which R is a lower alkoxy radical. 18. The method according to claim 1, characterized in that a compound of formula I obtained, in which R4 is a benzoyl group or a lower alkanoyl radical 30 means hydrolyzed to a corresponding compound of formula I in which R4 represents a hydrogen atom. 19. Use of new compounds of the general formula I in which R4 denotes a hydrogen atom, and their salts for the preparation of compounds of the 35 general formula I, in the R4 the rest X in which R3 and p have the above meaning and Y represents the radical R4-S or a halogen atom, or a reactive derivative thereof, and, if Y represents a halogen atom, reacting the intermediate obtained with a thiol of the formula R4-SH and optionally converting the compound obtained into a salt. 6. The method of claim 1, wherein R4 represents a benzoyl group. 7. The method of claim 1, wherein R represents a hydroxyl group. 8. The method according to claim I, in which p has the value 1. 9. The method of claim 1, wherein X represents an oxygen atom. R3 (R: -CH> I I -S- (CH2) p-CH-CO-N - (CH-Rl) n I. -CH-CO-R means, and their salts, characterized in that the compounds mentioned are oxidized and the compounds obtained are optionally converted into their salts.