DE2703828A1 - PROLINDER DERIVATIVES AND RELATED COMPOUNDS, METHODS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT - Google Patents

Description

"Proline Derivatives and Related Compounds, Process To their manufacture and use as a medicinal product "

Priority:

February 13, 1976, V.St.A., No. 657 792

June 21, 1976, V.St.A., No. 698 432

December 22, 1976, V.St.A. _i No. 751 851

The invention relates to proline derivatives and related compounds of general formula I.

₂ - p

(£ H) _ £ H- CO -

R.

ςΗ-COR

(D

in which R is a hydroxyl or araino group or a lower alkoxy group, R ₁ and R ^ are hydrogen atoms, lower alkyl groups, phenyl groups or phenyl-substituted lower alkyl groups, R _{2 is} a hydrogen atom, a lower alkyl group, a phenyl group or a halogen atom, a lower alkyl group , a lower alkoxy, a phenyl-substituted lower alkyl, a diphenyl-substituted lower alkyl, a triphenyl-substituted lower alkyl, a lower alkylthiomethyl, a phenyl-substituted lower alkylthiomethyl, a lower alkanoylamidomethyl radical or by one of the radicals

V-S-,

R ₅ -MC-,

R ₅ -NH-C-, Rc-S- or

709833/1005

substituted phenyl group, R ₃ denotes a hydrogen atom, a hydroxyl group or a lower alkyl group, R «denotes a lower alkyl group, a phenyl group or a phenyl-substituted lower alkyl group and Rg denotes a lower alkyl group, a phenyl group, a halogen atom, a lower alkyl group or a lower one Alkoxy-substituted phenyl group, a hydroxy-substituted lower alkyl or an amino- (carboxy) -substituted lower alkyl radical, R ™ represents the radical

(HC) CH R, R ₄

m *, 2 J ¹ J ⁴

_R _OC-HC - N - CO-CH- (CH) -S (O) * *

represents, M represents an oxygen or sulfur atom, m a value from 1 to 3 and η and ρ a value from 0 to 2 as well as their basic salts.

In general formula I, the asterisks denote asymmetric carbon atoms. Each of the carbon atoms to which the substituents R ₁ , R ^ and R ^ are bonded is a center of asymmetry if the substituent is not a hydrogen atom. The compounds of the general formula I can therefore exist as stereoisomers or as racemates. The invention relates both to the separate isomers and to their racemic mixtures. The enantiomers in which the asymmetric carbon atom of the amino acid is in the L configuration are preferred. Also preferred are the enantiomers in which the a-carbon atom in the acyl side chain, ie the carbon atom which _{bears the radical R 1} , is in the D form.

The salts can be derived from inorganic bases such as ammonia, alkali metals such as sodium and potassium, or alkaline earth metals such as calcium and magnesium or of organic bases, such as dicyclohexylamine, Ν, Ν'-dibenzyl-

709833/1005

ethylenediamine, N-methyl-D-glycamine, N, N'-bis (dehydroabietyl) ethylenediamine, or derived from amino acids such as arginine or lysine.

Non-toxic, physiologically acceptable salts are preferred, but other salts, such as the salts, can also be used Use dicyclohexylamine in an advantageous manner for isolating and cleaning the products.

The "lower alkyl radicals" are straight or branched Hydrocarbon residues with a maximum of 7 carbon atoms, Specific examples are the methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl, pentyl and isopentyl groups. The lower alkoxy radicals also contain a maximum of 7 carbon atoms. Specific examples are the Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy group. Preferred lower alkyl or Alkoxy radicals contain a maximum of 4 carbon atoms. Particularly the radicals with 1 or 2 carbon atoms are preferred. The preferred phenyl-substituted lower alkyl radical is Phenylmethyl group.

The "lower alkanoyl radicals" are acyl radicals of fatty acids with 2 to 7 carbon atoms. Specific examples are the acetyl, propionyl, butyryl and diisobutyryl groups. Preferably the lower alkanoyl radicals contain a maximum of 4 carbon atoms. The acetyl group is particularly preferred.

The halogen atoms are fluorine, chlorine, bromine and iodine atoms. Chlorine and bromine atoms are preferred.

The substituted phenyl radicals preferably carry the substituent in 4 position. The hydroxy-substituted lower ones Alkyl radicals have a hydroxyl group on an alkyl radical of the type described above, preferably at the terminal Carbon atom. Specific examples are the hydroxy

709833/1005

methyl and the 2-hydroxyethyl group. The amino (carboxy) substituted ones lower alkyl radicals have an amino and a carboxyl group on an alkyl radical of the type described above, preferably both on a carbon atom, for example on the terminal carbon atom, as in the preferred 2-amino-2-carboxyethyl group.

As a result of their properties, certain subgroups within the compounds of the general formula I are preferred. Preferred compounds of the general formula I are those in which R is a hydroxyl group or a lower alkoxy radical, R _{1 is} a hydrogen atom or a lower alkyl radical, R _{2 is} a hydrogen atom or one of the radicals Re-CO, Rg-S-, or Ry, R ? and R ^ hydrogen atoms, Rc a lower alkyl radical, especially a methyl or phenyl group, Rg a lower alkyl radical, especially a methyl or ethyl group, m is 2 and η is 0, 1 or 2, especially 1 and within the The radical Ry R, R ₁ , R ^, R ^, a and η have the same preferred meaning and ρ has the value 0.

The compounds of the general formula II are particularly preferred,

i ¹

R ₂ - S - (CH ₂ ) - CH-CO- N - _COR

in which R is a hydroxyl group or a lower alkoxy radical,

R _{1 is} a hydrogen atom or a lower alkyl radical, R _{2 is} a hydrogen atom or one of the radicals Rc-CO-, Rg-S- or Ry,

Rc is a lower alkyl radical or a phenyl group, especially a lower alkyl radical, and

Rg represents a lower alkyl radical and η the value 0.1 or 2 has.

709833/1005

\ b

Within the compounds of the general formula II, the following subgroups are in the order (a) to (r) Increasing preference highlighted as particularly preferred embodiments:

(a) R represents a hydroxyl group,

(b) η has the value 1,

(c) R ₂ denotes a hydrogen atom or a lower alkanoyl radical,

(d) R _{2 represents} a hydrogen atom,

(e) R _{2 represents} an acetyl group,

(f) R ₁ denotes a hydrogen atom or a lower alkyl radical,

(g) R ₁ denotes a hydrogen atom or a methyl group, (h) R denotes a hydroxyl group and R ₁ denotes a hydrogen atom or a methyl group,

(i) R is a hydroxyl group, R _{1 is} a hydrogen atom or a methyl group, R _{2 is} a hydrogen atom or

represents an acetyl group and η is 0, 1 or 2, (j) R represents a hydroxyl group, R ₁ and R ₂ each represent a

Hydrogen atom and η has the value 0, (k) R means a hydroxyl group, R ₁ a hydrogen atom,

R _{2 is} an acetyl group and η has the value 1, (l) R is a hydroxyl group, R _{1 is} a methyl group, R ₂

is an acetyl group and η is 1, (m) R denotes a hydroxyl group, R ₁ and R ₂ each represent a

Hydrogen atom and η has the value 1, (n) R means a hydroxyl group, R ₁ a methyl group,

a hydrogen atom and η has the value 1, (o) R denotes a hydroxyl group, R ₁ a hydrogen atom,

R _{2 is} a lower alkylthio radical and η has the value 1, (p) R ₂ denotes the radical

R-OC

R each is a hydroxyl group, R _{1 is} a hydrogen atom or a lower alkyl radical, especially a water

709833/1005

-N-OC-CH- (CH.) -S

substance atom or a methyl group and η has the value 0, or 2, especially 1, M
(q) R ₂ denotes the radical Rc-MC-,

where M represents an oxygen or sulfur atom,

(r) R ₂ denotes the radical R ₅ -NH-C-,

where M represents an oxygen or a sulfur atom, preferably a sulfur atom.

All possible combinations of the above definitions also belong to the preferred group of compounds.

The stereoisomers in which the proline is in the L-form are particularly preferred.

The compounds of the general formula I and their preferred subgroups can be prepared by various processes v / earth.

709833/1005

^{Cti) _m

HN CH - COR

with a carboxylic acid of the general formula IV

RR ₁

I ⁴ I ¹ - (IV)

R2 S- (CH) _n CH- COOH

or their chemical equivalent. This means that the compounds of the general formula I can be prepared not only by direct acylation with a carboxylic acid of the general formula IV, but also via suitable intermediates, for example by acylation with
(A) a cj -halocarboxylic acid of the general formula V.

(V)

X- (CH) -CH COOH

in which X is a chlorine, bromine or iodine atom, or (b) a p-tosyloxycarboxylic acid, i.e. in general Formula V, X denotes a p-tosyloxy radical

or

(c) a substituted acrylic acid of the general formula VI.

^r a ^R i

CH = C-COOH (VI)

The acylation products obtained are then a displacement or addition reaction with the anion of a Thiols or a thioacid of the general formula VII.

709833/1005

R ₂ -SH (VII)

The acylation can also be carried out with a thiolactone of the general formula VIII

f ⁴ ? 1 (VIII)

^(CH 2> n ^CH

- c _x
^N o

in which η has the value 1 or 2, or with a mercaptocar bonsäure of the general formula IX

j ⁴ I ¹

Y-S- (CII) CH -COK

(IX)

in which Y has the _{meaning given for R 2} , or a protective group, such as

^15> ^ s? ¹ ^

CH ₃ O- (O) -CH ₂ , C ₀ X, CH ₃ CONHCH ₂ , ROC-CH- (CH) _n -S-

if the compounds of the general formula I are to be prepared, in which R ₂ denotes a constituent atom. The protective group can be split off by known processes, for example by treatment with hot trifluoroacetic acid, cold trifluoromethanesulfonic acid, mercury acetate, sodium in liquid ammonia or with zinc and hydrochloric acid. An overview of the known processes for splitting off the protective group is given in Houben-Weyl, Methods of Organic Chemistry, Vol. 15, Part 1, 1974, pp. 736 ff.

When using carboxylic acids of the general formula IV as acylating agent, the acylation in the presence of a Coupling agents such as dicyclohexylcarbodiimide can be carried out, or the carboxylic acid can be converted into their mixed anhydride, symmetrical anhydride, acid chlo-

709833/1005

rid, ester or by using the Y / oodward reagent K, N-ethoxycarbonyl-2-ethoxy-i, 2-dihydroquinoline activated v / earth. An overview of the known acylation processes is in Houben-Weyl, Methods of Organic Chemistry, Vol. XV, Part II, 1974, pages 1 ff. Included.

Specific examples of suitable compounds of the general Formula III are proline, hydroxyproline, 4-methylproline, Piperidine-2-carboxylic acid, 5-hydroxypiperidine-2-carboxylic acid, Acetidine-2-carboxylic acid and its lower alkyl esters.

According to a preferred production process, the compounds of the general formula I, especially v / enn Rp den Rc-CO- radical means by reacting an amino acid or its ester of the general formula III with a halocarboxylic acid of the general formula V, in which X represents a halogen atom, preferably a chlorine or bromine atom. This reaction can be carried out by one of the known processes, the carboxylic acid being the general Formula V before the reaction with the compound of general formula III by conversion into a mixed anhydride, symmetrical anhydride, acid chloride, active ester or by using Woodward's reagent K or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline is activated. The implementation described is a connection of the general formula X obtained.

R. R ₁ H ₀ C (CH)

| 4, 1 2., m

X (CH) CH-CO-N CH-COR

The compound of the general formula X can be reacted, for example, with the anion of a thioacid of the general formula VII to form a compound of the general formula I. If R ₂ in the compound obtained the general

709833 / 100B

Formula I represents the radical Rc-CO-, the compound of the general formula I in which R _{2 is} a hydrogen atom can be obtained by ammonolysis. If R _{2 represents} a protective group, it can be split off by one of the processes described above. If R in the compound of the general formula I obtained is an ester radical, for example a tert-butoxy or tert-amyloxy group, this can be split off by reaction with trifluoroacetic acid and anisole. This gives the corresponding free carboxylic acid. Other alkoxy radicals can be converted into the carboxyl group by alkaline hydrolysis.

In another embodiment, the acylation with a substituted acrylic acid of the general formula VI be performed. To do this, the acrylic acid is first converted into the acid halide, and then with a compound of the general formula III to a compound of the general formula XI

(XI)

CH = C-CO-N CH-COR

reacted, which then, as described above, treated with the thiol or the thioacid of the general formula VII will.

A p-tosyloxycarboxylic acid can also be used as acylating agent of the general formula XII

CH ₃ - ^ o) -SO ₂ O- (CH) -CH-COOH (XIl)

be used. The intermediate obtained is as above described further treated.

709833/1005

In a further embodiment, the substituted Acrylic acid of the general formula VI initially with the thio acid of the general formula VII to a compound of the general formula XIII

? ⁴ f ¹ (XIII)

R ₂ -S-CH-CH-COOH

are implemented, which then for example .mit thionyl chloride converted into their acid halide and then reacted with a compound of the general formula III will.

The compounds of the general formula III can also be replaced by a u) mercaptocarboxylic acid of the general formula XIV

^R A ^R l

I I

R ₀ -S- (CH) -CH-COOH (XIV)

ο π

are acylated, in which R _{Q is} one of the protective groups described above. After the acylation, the protective group can be split off by one of the known processes described above.

Further suitable acylating agents are thiolactones, such as ß-propiothiolactone or α-methyl-ß-propiothiolactone.

In a particularly preferred embodiment of the inventive device Process, the compounds of general formula III with a halocarboxylic acid halide of the general formula XV

4 * l (XVj

X- (CH) -CH-COX

709833/1005

acylated, in which X is a halogen atom, preferably a chlorine or chromate atom and Rj is a hydrogen atom, a lower alkyl radical or a phenyl-substituted lower alkyl radical and η is 0, 1 or 2. This reaction is in the presence of a base such as dilute alkali solution, Alkaliraetallbicarbonat- or carbonate solution at a low temperature, for example about 0 to 15 ⁰ C.,. The intermediate product obtained is also reacted in the presence of a base, preferably an alkali metal carbonate solution, with the anion of a thiol or a thioacid of the general formula VII, and then worked up in a known manner. If the compound of the general formula I 1 * 2 is the radical R ^ -CO-, it can be prepared by ammonolysis, for example with concentrated ammonia or with a solution of ammonia in an alcohol, or by alkaline hydrolysis, for example with a metal hydroxide solution, into the compound of the general formula I in which R _{2 is} a hydrogen atom. If the compound of general formula III used is the free carboxylic acid, the resulting carboxylic acid of general formula I can be obtained by esterification with a diazoalkane, such as diazomethane, or with an i-alkyl-3-p-tolyl-triazene, such as in-butyl- 3-p-tolyltriazine, can be converted into an ester. The ester, preferably the methyl ester, can in turn be converted into the corresponding carboxamide by treatment with a solution of ammonia in an alcohol.

In another embodiment, an ester, preferably the tert-butyl ester, of the general formula III in one anhydrous medium, such as methylene chloride, tetrahydrofuran or dioxane, with a thiocarboxylic acid of the general formula XVI

709833/1005

reacted in the presence of dicyclohexylcarbodiimide, Ν, Ν'-carbonylbisimidazole, ethoxyacetylene, diphenylphosphorylazide or a similar coupling agent at a temperature of about 0 to 10 ⁰ C. The ester residue can then be split off, for example, by treatment with trifluoroacetic acid and anisole at room temperature.

The reaction of an ester of the general formula III, in which R is a lower alkoxy radical, preferably a tert-butoxy group, with a thiolactone such as β-propiothiolactone or α-methyl-β-propiothiolactone can be carried out in an anhydrous solvent such as tetrahydrofuran, dioxane or methylene chloride, are carried out at temperatures from about 0 ^° C. to room temperature. The ester residue can be split off with trifluoroacetic acid and anisole as described above.

The compounds of general formula I in which R ~ is the remainder

M.
II

R ₅ -MC-

means can by implementing an appropriate compound of the general formula I, in which R ~ is a hydrogen atom means with a compound of the general formula XVII

R ₅ -MCX

or by reacting a compound of the general formula X with an alkali or alkaline earth metal salt of the general formula Formula XVIII

^M (XVIII)

R ₅ -MCS-Me

709833/1005

in which Me is an alkali or alkaline earth metal atom will.

The compounds of general formula I in which R _{2 is} the remainder

M.
R ₅ -NH-C-

means are obtained by reacting the corresponding compound of the general formula I, in which R _{2 is} a hydrogen atom, with an appropriately substituted isocyanate or isothiocyanate of the general formula XIX

R ₅ -N = C = M (XIX)

manufactured.

In another embodiment, the same compounds can also by reacting a carboxylic acid of the general formula XX

Mr r

Il I \ r- IaA;

R-NH-C-S- (CH) CH-COOH

3 η

be prepared with a compound of the general formula III.

The compounds of general formula I in which R _{2 is} a lower alkyl radical, a phenyl or substituted phenyl group, a phenyl or triphenyl-substituted lower alkyl radical, a lower alkylthiomethyl or a phenyl-substituted lower alkylthiomethyl radical, are obtained by reacting the compounds of general formula I, in which R ₂ denotes a hydrogen atom, with a corresponding halide of the general formula R ₂ X or by reacting the compound of the general formula X with a corresponding thiol of the general formula R ₂ SH in the manner described above.

709833/1005

-λ-

The compounds of the general formula I in which R _{2 is} a lower alkanoylamidomethyl radical are obtained by reacting the compounds of the general formula I in which Rp is a hydrogen atom with the corresponding hydroxymethyl-substituted lower alkanoyl amide of the general formula XXI

Alkyl-CO-NHCH ₂ OH (XXI).

obtained in the presence of an acidic catalyst such as trifluoroacetic acid.

The compounds of the general formula I in which R ₂ denotes the radical Rg-S- can be obtained by one of the known processes for the preparation of mixed disulfides, for example by reacting the compounds of the general formula I in which R ₂ denotes a hydrogen atom , with a thiosulfinate of the general formula XXII, a thiosulfonate of the general formula XXIII, a sulfenyl halide of the general formula XXIV, a thiosulfate of the general formula XXV or a sulfenyl thiocyanate of the general formula XXVI.

O O

R ₆ -SSR ₆ , R ₆ -SSR ₆ , R ₆ SX, R ₆ -S-SO ₃ H, Rg-S-SCN

O
(XXII) (XXIII) (XXIV) (XXV) (XXVI)

The compounds of general formula I in which Ry is the rest

? 4 fl f ^H 2— »

-S (O) (CH) CH-CO-N CH-COR

P η

means in which R, R ₁ , R ₅ and R ^ have the meaning given above and ρ has the value 0, can be obtained _{with iodine by direct oxidation of the compounds of the general formula I in which R 2 is} a hydrogen atom. the

709833 / 100S

Compounds in which ρ has the value 1 or 2 are obtained by stepwise oxidation of the corresponding compounds, in which ρ has the value O. The preparation of mixed disulfides is illustrated in the examples.

Ih the preparation process described above, the starting compounds as racemates or as separate Enantiomers are used. When using the racemates, the products obtained can by customary chromatographic Process or by fractional crystallization are split into the stereoisoraere.

The salts are prepared in a known manner by reacting the free acids with at least one equivalent of the corresponding base in a solvent in which the salt is insoluble, or in water, the water being removed by freeze-drying. The salts can in turn be converted into the free acids or, if appropriate, into another salt with a cation exchanger in the H ⁺ form, for example a polystyrene sulfonate resin, or with a dilute acid and subsequent extraction with an organic solvent such as ethyl acetate or methylene chloride. earth.

The compounds of the general formula I are valuable medicinal substances. They prevent the conversion of the decapeptide angiotensin I into angiotensin II and reduce or eliminate it hence the hypertension caused by angiotensin. Angiotensin I is produced by the action of the enzyme renin Angiotensinogen, a pseudoglobulin found in the blood plasma. Angiotensin I is converted into Angiotensin II converted. The latter is an active antihypertensive compound and is responsible for various Forms of hypertension in rats and dogs, for example.

The compounds prepared by the process of the invention intervene in the implementation sequence Angiotensinogen (Renin) -: Angiotensin I ---> Angiotensin II by blocking the angiotensin converting enzyme and thereby the development

709833/1005

reduce or switch off the blood pressure increasing compound angiotensin II. Administration of compounds of general As a result, formula I or its physiologically tolerable salts alleviates those caused by angiotencin Hypertension. A single dose, or preferably two to four divided daily doses of about 0.1 to 100 mg, preferably from about 1 to 50 rag / kg / day is suitable for a reduction in blood pressure, as in that of S.L. Engel, T.R. Schaeffer, M.H. Waugh and B. Rubin, Proc. Soc. Exp. Biol. Med., Vol. 143, 1973, p. 483 described animal experiment will be shown.

The compounds of general formula I can be taken orally or administered parenterally in the usual dosage forms.

709833/1005

example 1
1- (2-Benzovlthioacetyl) -L-T> roline

5.75 g of L-proline are dissolved in 50 ml of 1 n sodium hydroxide solution and chilled in an ice water bath. The solution obtained is mixed with 26 ml of 2 η sodium hydroxide solution and 5.65 g of chloroacetyl chloride and stirred vigorously for 3 hours at room temperature. Thereafter - the reaction mixture with a suspension of 7.5 g of thiobenzoic acid and 4.8 g of potassium carbonate in 50 ml of water are added and the mixture is stirred at room temperature for 18 hours. Then will the reaction mixture acidified and extracted with ethyl acetate. The ethyl acetate layer is separated, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. There are 14.6 g of residue obtained, which is dissolved in 150 ml of ethyl acetate and mixed with 11 ml of dicyclohexylamine. The resulting crystals are filtered off and unicrystallized from ethyl acetate. Yield: 5.7 g, mp 151 to 152 ° C. For conversion of the salt in the free acid are the crystals in a mixture of 100 ml of 5 percent potassium bisulfate solution and 300 ml of ethyl acetate dissolved. The organic phase is separated off, washed once with water and dried over magnesium sulfate and evaporated to dryness under reduced pressure. Yield: 3.45 g of the title compound.

Example 2 1- (2-Mercaptoacetvl) -L-proline

3.4 g of 1- (2-benzoylthioacetyl) -L-proline are dissolved in a mixture of 10.5 ml of water and 6.4 ml of concentrated ammonia. After 1 hour the mixture is diluted with water and filtered off. The filtrate is extracted with ethyl acetate and then acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted twice with ethyl acetate. The ethyl acetate extracts are then combined, washed with saturated sodium chloride solution and evaporated to dryness. Yield: 1.5 g of the title compound with a melting point of 133 to L · J

709833/1005

135 ° C after recrystallization from ethyl acetate.

Example3
1- (2-Benzovlthioacetyl) -L-proline methyl ester

The 1- (2-benzoylthioacetyl) -L-proline obtained according to Example 1 is dissolved in methanol and treated with a solution of diazomethane added in diethyl ether until a permanent yellow color. After 15 minutes the reaction mixture becomes a few drops of acetic acid are added and the solvent is distilled off under reduced pressure. It becomes the title compound obtain.

Example 4
1- (2-mercaptoacetyl) -L-proline amide

The compound prepared according to Example 3 is in a 10 percent solution of ammonia dissolved in methanol and stored in a pressure vessel at room temperature. If the Thin-layer chromatographic analysis shows the ammonolysis of the two ester functions, the reaction mixture is used to Evaporated dry. The title compound is obtained.

Example 5 1- (2-Benzovlthioacetyl) -L-hydroxylproline

Example 1 is repeated with the change that LfProlin / L-hydroxyproline is used instead of LfProlin. It becomes the title compound obtain.

Example 6 1- (2-Mercaptoacetyl) -L-hvdroxvprolin

The compound prepared according to Example 5 is reacted with ammonia according to Example 2 to give the title compound.

Example 7 1- (2-Benzovlthioacetvl) -L-azetidine-2-carboxylic acid

Example 1 is repeated with the change that L-proline / L-azetidine-2-carboxylic acid is used instead of L-proline. It will be _j

709833/1005

obtained the title compound.

Example 8 1- (2-Mercaptoacetvl) -L-azetidine-2-carboxylic acid

The compound obtained according to Example 7 is reacted with ammonia according to Example 2 to give the title compound.

Example 9
1- (2-Benzovlthioacetyl) -L-piperidine-2-carboxylic acid

Example 1 is repeated with the change that L-proline / L-piperidine-2-carboxylic acid is used instead of L-proline. It the title compound is obtained.

Example 10 1- (2-Mercaptoacetvl) -L-piperidine-2-carboxylic acid

The compound obtained according to Example 9 is reacted with ammonia according to Example 2 to give the title compound.

Example 11
1- (2-Benzovlthiopropanovl) -L-proline

5.75 g of L-proline are dissolved in 50 ml of 1 n sodium hydroxide solution. the The solution obtained is cooled with stirring in an ice bath and then successively with 25 ml of 2 η sodium hydroxide solution and 8.57 g 2-bromopropionyl chloride added. Then the mixture is made taken the ice bath and stirred for 1 hour at room temperature. The reaction mixture is then mixed with a mixture 7.5 g of thiobenzoic acid and 8.4 g of potassium carbonate in 50 ml of water are added and at room temperature for about 15 hours touched. The reaction mixture is then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. Of the Ethyl acetate extract is washed with water, dried and evaporated to dryness. 14.7 g of residue are obtained that on a column with 44 g of silica gel with a mixture of benzene and acetic acid in a volume ratio of 7: 1 as the mobile phase is chromatographed. The fractions containing the product are collected and evaporated to dryness. The received

709833/1005

The residue is reprecipitated twice from a mixture of diethyl ether and hexane and finally in a mixture converted into the dicyclohexylamine salt by diethyl ether and hexane as solvents. Yield 9.4 g of F. (142) 148 to 156 ° C. The dicyclohexylamine salt is converted into the free acid according to Example 1. Yield 5.7 g of the title compound.

Example 12 1 - (2-Mei-captopropanovl) -L-proline

5.7 g of 1- (2-benzoylthiopropanoyl) -L-proline are dissolved in a mixture of 12 ml of water and 9 ml of concentrated ammonia with stirring. After 1 hour the mixture is diluted with 10 ml of water and filtered off. The filtrate is then extracted twice with ethyl acetate, concentrated to a third of its original volume, acidified with concentrated hydrochloric acid and extracted again with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue obtained is recrystallized from a mixture of ethyl acetate and hexane. Yield 3 g of the title compound of F. (105) 116 to 120 ^° C.

Example 13 i - ^ - BenzovlthiopropanovlJ-L-proline

5.75 g of L-proline are dissolved in 50 ml of 1 n sodium hydroxide solution. The resulting solution is cooled in an ice bath and then 8.5 g of 3-bromopropionyl chloride and 27 ml of 2 η sodium hydroxide solution are added. The mixture is then stirred in an ice bath for 10 minutes and at room temperature for 3 hours. A suspension of 7.5 g of thiobenzoic acid and 4.5 g of potassium carbonate in 50 ml of water is then added to the mixture, and the mixture is stirred at room temperature for 18 hours. After acidification with concentrated hydrochloric acid, the aqueous phase is extracted twice with ethyl acetate. The ethyl acetate extracts are combined, dried over magnesium sulfate and evaporated to dryness under reduced pressure. Yield: 7.1 g of the Ti ⁺ el compound with a melting point of 101 bis

709833/1005

102 ⁰ C after recrystallization from a mixture of ethyl acetate and hexane.

Example 14 L-proline tert-butyl ester

230 g of L-proline are dissolved in a mixture of 1 liter of water and 400 ml of 5 n sodium hydroxide solution. The solution obtained is cooled in an ice bath and then, with vigorous stirring, 460 ml of 5 n sodium hydroxide solution and 340 ml of benzyloxycarbonyl chloride are added in five equal portions over the course of 1/2 hour. The mixture is then stirred for 1 hour at room temperature, then extracted twice with diethyl ether and acidified with concentrated hydrochloric acid. The precipitate obtained is filtered off and dried. Yield 442 g with a melting point of 78 to 8O ⁰ C.

180 g of the benzyloxycarbonyl-L-proline obtained are in dissolved in a mixture of 300 ml of methylene chloride, 800 ml of liquid isobutylene and 7.2 ml of concentrated sulfuric acid. The resulting solution is shaken in a pressure vessel for 72 hours. The pressure is then released, the isobutylene evaporated and the remaining solution with a 5 percent sodium carbonate solution and washed with water, dried over magnesium sulfate and under reduced pressure evaporated to dryness. Yield: 205 g of benzyloxycarbonyl-L-proline tert-butyl ester.

205 g of this compound are dissolved in 1.2 liters of anhydrous ethanol and hydrogenated using 10 g of 10 percent palladium-on-carbon at normal pressure until only traces of carbon dioxide are found in the emerging hydrogen gas (24 hours). The catalyst is then filtered off and the filtrate is evaporated under a pressure of 30 torr. The residue obtained is distilled under reduced pressure. The title _{compound with a boiling point of} 50 ° to 51 ° C. is obtained.

709833/1005

Example 15 1- (3-acetyl thiopropanovl) -L-proline-tert-butyl ester

5.13 g of L-proline tert-butyl ester are dissolved in 40 ml of methylene chloride solved. The resulting solution is cooled in an ice-water bath with a solution of 6.18 g of dicyclohexylcarbodiimide in 20 ml of methylene chloride and then immediately mixed with 4.45 g of 3-acetylthiopropionic acid. The mixture is then Stirred in the ice-water bath for 15 minutes and at room temperature for 16 hours. Then the resulting precipitate becomes filtered off and the filtrate evaporated to dryness under reduced pressure. The residue is dissolved in ethyl acetate and washed until neutral. The organic layer is then separated off and dried over magnesium sulfate and evaporated to dryness under reduced pressure, yield: 9.8 g of the title compound.

Example 16 1- (3-Acetylthlopropanovl) -L-proline

4.7 g of 1- (3-acetylthiopropanoyl) -L-proline tert-butyl ester are dissolved in a mixture of 34 ml of anisole and 68 ml of trifluoroacetic acid. The resulting mixture is kept at room temperature for 1 hour. The solvents are then distilled off under reduced pressure and the residue obtained is reprecipitated several times from a mixture of diethyl ether and hexane. 3.5 g of residue are obtained, which are dissolved in 25 ml of acetonitrile and treated with 2.8 g of dicyclohexylamine. The crystalline precipitate obtained is filtered off and recrystallized from isopropanol. Yield: 3.8 g, mp 176-177 ⁰ C. According to Example 1 from the salt 1.25 g of the title compound, melting at 89 or 90 ° C after recrystallization from a mixture of ethyl acetate and hexane obtained.

709833/1005

Example 17 1- (3-Mercaptopropanovl) -L-proline-tert-butyl ester

A solution of 3.2 g of L-proline tert-butyl ester in 10 ml of anhydrous tetrahydrofuran is cooled in an ice bath and 1.76 g of propiothiolactone are added . The mixture obtained is kept in an ice bath for 5 minutes and then at room temperature for 3 hours and then diluted with 200 ml of ethyl acetate and washed with a 5 percent potassium bisulfate solution and with water. The organic layer is separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained is recrystallized from a mixture of diethyl ether and hexane. Yield: 3.7 g of the title compound with a melting point of 57 to 58 ^° C.

Example 18 1- (3-Mercaptopropanovl) -L-proline

Method A:

4.9 g of 1- (3-benzoylthiopropanoyl) -L-proline are dissolved in a mixture of 8 ml of water and 5.6 ml of concentrated ammonia and stirred for 1 hour under argon as a protective gas. The reaction mixture is then diluted with water and filtered off and the filtrate is extracted with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extracts are then combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained is recrystallized from a mixture of ethyl acetate and hexane. Yield 2.5 g of the title ^{compound with a melting point of 68 to 70 °}

V »·

Method B:

0.8 g of 1- (3-acetylthiopropanoyl) -L-proline are in 5 ml 5.5 η solution of ammonia dissolved in methanol and stored under argon as a protective gas for 2 hours at room temperature. The solvent is then distilled off under reduced pressure, the residue is taken up in water and passed through

709833/1005

SO

a cation exchanger in the H ⁺ form with water as the mobile phase. The product-containing fractions are collected and evaporated to dryness. Yield 0.6 g of the title compound, which is recrystallized from a mixture of ethyl acetate and hexane.

Method C:

2.3 g of 1- (3-mercaptopropanoyl) -L-proline tert-butyl ester will be dissolved in a mixture of 20 ml of anisole and 45 ml of trifluoroacetic acid. The resulting mixture is taken for 1 hour Argon stored as a protective gas at room temperature and then evaporated to dryness under reduced pressure. The residue will be several times. reprecipitated from a mixture of ethyl acetate and hexane. 1.9 g of residue are obtained which is dissolved in 30 ml of ethyl acetate and treated with 1.85 ml of dicyclohexylamine. The resulting crystalline precipitate is filtered off and recrystallized from isopropanol. Yield 2 g with a melting point of 187 to 188 ° C. According to example 1 this will be Salt converted into the free acid. Yield: 1.3g. That Product is recrystallized according to method A from a mixture of ethyl acetate and hexane.

Production of do-r salts

500 mg of 1- (3-mercaptopropanoyl) -L-proline are used in a mixture dissolved by 2.5 ml of water and 2.5 ml of 1 η sodium hydroxide solution. The sodium salt is obtained by freeze drying.

500 mg 1- (3-mercaptopropanoyl) -L-proline, 49.5 mg magnesium oxide and 10 ml of water are stirred with slight warming until completely dissolved. By freeze drying the solution the magnesium salt is obtained.

500 mg of 1- (3-mercaptopropanoyl) -2-proline are in a mixture dissolved by 91 mg of calcium hydroxide and 10 ml of water. The calcium salt is obtained by freeze drying the solution.

709833/1005

'3Ι \

500 mg of 1- (3-mercaptopropanoyl) -L-proline are dissolved in a mixture of 246 mg of potassium bicarbonate and 10 ml of water. The potassium salt is obtained by freeze drying the solution.

500 mg of 1- (3-mercaptopropanoyl) -L-proline and 480 mg of N-methyl-D-glycamine are dissolved in 10 ml of water. The N-methyl-D-glycamine salt is obtained by freeze-drying.

Example 19 1- (3-Mercaptopropanovl) -L-hvdroxvprolin

Example 11 is repeated with the change that instead of is used by L-Prolin yL-Hydroxyproline. The received 1- (3-Benzoylthiopropanoyl) -L-hydroxyproline is then converted to the title compound according to Example 18, Method A.

Example 20 1- (3-Mercaptopropanovl) -L-azetidine-2-carboxylic acid

Example 14 is repeated with the change that L-azetidine-2-carboxylic acid is used instead of L-proline. The resulting L-azetidine-2-carboxylic acid tert-butyl ester is reacted in place of the L-proline tert-butyl ester according to Example 15 and the resulting "1- (3-acetylthiopropanoyl) -L-azetidine-2-carboxylic acid tert The.-butyl ester is treated according to Example The title compound is obtained by reacting the 1- (3-acetylthiopropanoyl) -L-azetidine-2-carboxylic acid obtained according to Example 18, method B _1.

Example 21 1- (3-Mercaptopropanovl) -L-pjperidin-2-carboxylic acid

Example 14 is repeated with the change that instead of of L-proline / L-piperidine-2-carboxylic acid is used. The tert-butyl L-piperidine-2-carboxylate obtained is implemented according to Example 15 instead of the L-proline tert-butyl ester. The obtained 1- (3-mercaptopropanoyl) -L-

709833 / 100S

piperidine-2-carboxylic acid tert-butyl ester is according to Example 18, process C> converted to the title compound.

Example 22 1- (5-Mercaptopropanovl) -4-methyl-L-proline

Example 13 is repeated with the change that ^ -methyl-L-proline is used instead of L-proline. Afterward the 1- (3-benzoylthiopropanoyl) -4-methyl-L-proline obtained is converted to the title compound according to Example 18, method A.

Example 23 1- (3-MercaptoproT3anovl) -5-hydroxy-L-piperidine-2-carboxylic acid

Example 13 is repeated with the change that instead of L-proline / 3-hydroxy-L-piperidine-2-carboxylic acid is used will. The 1- (3-benzoylthiopropanoyl) 5-hydroxy-L-piperidine-2-carboxylic acid obtained is then used according to Example 18, process Λ, converted to the title compound.

Example 24 1- (3-mercaptopropanoyl) -D-proline

Example 13 is repeated with the change that instead of L-proline / D-proline is used. Subsequently, the obtained 1- (3-Benzoylthiopropanoyl) -D-proline according to Example 18, Method A, to give the title compound, melting at 68 to 7O ⁰ C is reacted.

Example 25 3-Acetylthio-2-methylpropionic acid

A mixture of 50 g of thioacetic acid and 40.7 g of methacrylic acid is heated on the steam bath for 1 hour and then kept at room temperature for 18 hours. Then through NMR spectroscopy found that the methacrylic acid has reacted completely. The reaction mixture is then under distilled under reduced pressure. Yield 64 g of the title

709833/1005

bond from b.p. 128.5 to 131 ° C 2.6 Torr.

Example 26 3-Benzovlthio-2-methyltropionic acid

Example 25 is repeated with the change that instead of

the
of thioacetic acid / xhiobenzoe,

obtained the title compound.

the
of thioacetic acid / xhiobenzoic acid is used. It will

Example 27

3-phenyl acetylthio-2-methyl ropionic acid

Example 25 is repeated with the change that aßiiophenylacetic acid is used instead of thioacetic acid. It the title compound is obtained.

Example 28

1- (3-Acetyl thio ~ 2-methvlT) ropanovl) -L-proline-tert-butyl ester

5.1 g of L-proline tert-butyl ester are dissolved in 40 ml of methylene chloride solved. The resulting mixture is stirred while cooling in an ice bath with a solution of 6.2 g of dicyclohexylcarbodiimide in 15 ml of methylene chloride and immediately thereafter with a solution of 4.9 g of 3-acetylthio-2-methylpropionic acid added in 5 ml of methylene chloride. Subsequently, the resulting mixture is 15 minutes in an ice bath and then 16 hours stirred at room temperature. The precipitate formed is then filtered off and the filtrate is reduced under reduced pressure Pressure evaporated to dryness. The residue obtained is dissolved in ethyl acetate and washed until neutral. The organic phase is separated off, dried over magnesium sulfate and brought to dryness under reduced pressure evaporated. The residue obtained is purified by chromatography on a silica gel column using chloroform as the mobile phase. Yield 7.9 g of the title compound.

709833 / 100S

Example 29

1- (3-acetylthio-2-methylpropanoyl) -L-proline Method A:

7.8 g of the 1- (3-acetylthio-2-methylpropanoyl) -L-proline tert-butyl ester prepared according to Example 28 are dissolved in 55 ml of anisole and 110 ml of trifluoroacetic acid. The mixture obtained is stored at room temperature for 1 hour, then the solvent is distilled off under reduced pressure and the residue is repeatedly precipitated from a mixture of diethyl ether and hexane. 6.8 g of the residue are then dissolved in 40 ml of acetonitrile, and 4.5 ml of dicyclohexylamine are added. The resulting crystalline precipitate is filtered off and boiled with 100 ml of freshly distilled acetonitrile. The mixture is then cooled to room temperature and filtered off. Yield: 3.8 g of the temperature (165) 187 to 188 ^° C. The compound is recrystallized from isopropanol. It has a specific rotation / α / _Ώ of -67 ° (C 1.4, ethanol).

The crystalline dicyclohexylamine salt is suspended in a mixture of 5 percent potassium bisulfate solution and ethyl acetate. The organic phase is then separated off, washed with water and evaporated to dryness. The received The residue is obtained from a mixture of ethyl acetate and hexane

recrystallized in the 2D form. It is the title compound, melting at 83 to 85 ⁰ C, / α / ρ ^5: receive -162 ° (C 1.7, ethanol).

Procedure Bt

A suspension of 8.1 g of 3-acetylthio-2-methylpropionic acid and 7 g of thionyl chloride is 16 hours at room temperature touched. The reaction mixture then becomes dry evaporated and distilled under reduced pressure (boiling point 80 ° C). 5.4 g of the 3-acetylthio-2-methylpropionic acid chloride obtained and 15 ml of 2 η sodium hydroxide solution become a solution of 3.45 g of L-proline in 30 ml of 1 η sodium hydroxide solution given, which was cooled in an ice-water bath. Afterward

709833 305

the mixture is stirred for 3 hours at room temperature and then extracted with diethyl ether. The aqueous phase is acidified and extracted with ethyl acetate. The organic phase is then dried over magnesium sulfate and evaporated to dryness. 1- (3-Acetyl thio-2-DL-methylpropanoyl) -L-proline is obtained.

Method C;

A solution of 3.45 g of L-proline in a mixture of 100 ml Water and 12 g of sodium bicarbonate are cooled in an ice-water bath and 4.16 g of methacryloyl chloride are added with vigorous stirring. After that, the resulting mixture is 2 hours stirred at room temperature and then extracted with diethyl ether. The aqueous phase is acidified with 1 η hydrochloric acid and extracted with ethyl acetate. The organic phase is evaporated to dryness under reduced pressure, the residue is mixed with 3.5 g of thiolacetic acid, mixed with a few crystals of azobisisobutyronitrile and 2 hours heated in the steam bath. Thereafter, the reaction mixture is in a mixture of benzene and acetic acid in a volume ratio 75:25 and chromatographed on a silica gel column with the same solvent. It becomes 1- (3-acetylthio-2-DL-methylpropanoyl) -L-proline obtain.

Example 3o 1- (3-Benzovlthio-2-methylpropanovl) -L-proline tert-butyl ester

Example 28 is repeated with the change that instead of 3-acetylthio-2-methylpropionic acid, 3-benzoylthio-2-methylprop Ionic acid is used. The title compound is obtained.

Example 31

1 - (3-Phenylacetylthlo-2'-methylpropanoyl) -L-proline-tert. -butvlester

Example 28 is repeated with the change that instead of of 3-acetylthio-2-methylpropionic acid, the 3-phenylace-

709833/1005

tylthio-2-methylpropionic acid is used. It will obtained the title compound.

Example 32 1- (5-Benzovlthio »2-methylpropanovl) -L-proline

Example 29, Procedure A, is repeated with the change, that instead of 1- (3-acetylthio-2-methylpropanoyl) -L-proline tert-butyl ester the 1- (3-benzoylthio-2-methylpropanoyl) -L-proline tert-butyl ester is used. It will be the Title compound obtained.

Example 33 1- (3-Phenyllactylthio-2-methylpropanovl) -L-proline

Example 29, Procedure A, is repeated with the change, that instead of 1- (3-acetylthio-2-methylpropanoyl) -L-proline tert-butyl ester the 1- (3-phenylacetylthio-2-methylpropanoyl) -L-proline tert-butyl ester is used. It is obtained, the title compound.

Example 34 1- (5-Mercapto-2-D-roethylpropanoyl) -L-proline

1- (3-Mercapto-2-methylpropanoyl) -L-proline is made from the products of Examples 29, 32 and 33 prepared as follows:

0.85 g of the thioester are dissolved in a 5.5 μm solution of ammonia in methanol and stored for 2 hours at room temperature. The solvent is then distilled off under reduced pressure and the residue is dissolved in water. The solution obtained is passed through a cation exchanger in the H ⁺ form and eluted with water. The fractions with a positive thiol reaction are collected and freeze-dried. The residue obtained is recrystallized from a mixture of ethyl acetate and hexane. Yield: 0.3 g. The title compound has a temperature of 103 to 104 ⁰ C and a / ά / _η of -131 ° (C 2, ethanol).

709833/1005

'TY

Example 35 1- (3-Acetylthio-2-metholpropanoyl) -L-proline methoxide

According to Example 3 there is 1- (3-acetylthio-2-methylpropanoyl) -L-proline reacted with a solution of diazomethane in diethyl ether. The title compound is obtained.

Example 36

1- (3-Mercapto-2-methylpropanoyl) -L-proline amide

Example 4 is repeated with the change that instead of 1- (2-B3nzoylthioacetyl) -L-proline methyl ester the 1- (3-Acetylthio-2-methylpropanoyl) -L-proline methyl ester was used will. The title compound is obtained.

Example 37 3-Acetylthio-2-benzylpropionic acid

Example 25 is repeated with the change that instead of

the
of methacrylic acid ^ -Benzylacryläure is used. The title compound is obtained.

Example 38 1- (3-Acetylthio-2-benzylpropanovl) -L-proline tert-butyl ester

Example 2.8 is repeated with the change that instead of 3-acetylthio-2-methylpropionic acid, 3-acetylthio-2-benzylprop Ionic acid is used. The title compound is obtained.

Example 39 1- (3-Acetylthio-2-benzylpropanovl) -L-prolln

Example 29, method A, is repeated with the change that instead of the 1- (3-acetylthio-2-methylpropanoy]) - L-proline tert-butyl ester the 1- (3-acetylthio-2-benzylpropanoyl) -L-proline tert-butyl ester is used. The title compound is obtained.

709833/1005

Example 40 1- (3-Mercapto-2-benzylpropanovl) -L-proline

According to Example 34, 1- (3-acetylthio-2-benzylpropanoyl) -L-proline is treated with a solution of ammonia in methanol. The title compound is obtained in the form of an oil, R _£ = 0.47 (silica gel, benzene / acetic acid in a volume ratio of 75:25).

Example "41 1- (3-mercapto-2-methvlpropanovl) -L-hvdroxvprolin

Example 28 is repeated with the change that instead of the L-proline tert-butyl ester, the L-hydroxyproline tert «- butyl ester is used. The 1- (3-acetylthio-2-methylpropanoyl) -L-hydroxyproline tert-butyl ester obtained becomes 1- (3-acetylthio-2-methylpropanoyl) -L-hydroxyproline according to Example 29, method A implemented, from which the title compound is then obtained according to Example 34.

Example 42 1- (5-Merce.T3to-2-methvlpropanovl) -L-azetidine-2-carboxylic acid

Example 28 is repeated with the change that, instead of the L-proline tert-butyl ester, the L-azetidine-2-carboxylic acid tert-butyl ester is used. The obtained 1- (3-acetylthio-2-methylpropanoyl) -L-azetidine-2-carboxylic acid tert-butyl ester is according to Example 29, method A, to 1- (3-acetyl thio-2-methylpropanoyl) -L-azetidine-2-carboxylic acid implemented, from which the title compound is obtained according to Example 34.

Example 43 1- (3-MercaOto-2-methylpropanovl) -L-piperidine-2-carboxylic acid

Example 28 is repeated with the change that, instead of the L-proline tert-butyl ester, the L-piperidine-2-carboxylic acid tert-butyl ester is used. The tert-butyl 1- (3-acetyl thio-2-methylpropanoyl) -L-piperidine-2-carboxylate obtained is according to Example 29, method A,

709833/1005

to 1- (3-acetylthio-2-methylpropanoyl) -L-piperidine-2-carboxylic acid implemented, from which the title compound is obtained according to Example 34.

Example 44 1- (4-Benzovlthiobutanoyl) -L-proline

A solution of 2.88 g of L-proline in 25 ml of 1 η sodium hydroxide solution is cooled in an ice bath, and 12.5 ml of 2 η sodium hydroxide solution and 3.5 g of 4-chlorobutyryl chloride are added. The mixture is then stirred for 3-5 hours at room temperature and a suspension of 3.75 g of thiobenzoic acid and 2.4 g of potassium carbonate in 25 ml of water is then added. The resulting mixture is stirred for about 15 hours at room temperature, then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained is then chromatographed on a silica gel column with a mixture of benzene and acetic acid in a volume ratio of 7: 1. The product-containing fractions are collected and evaporated to dryness. Yield: 1.35 g of the title compound. A small amount of this compound is dissolved in ethyl acetate and dicyclohexylamine is added to a pH of 8-10. The dicyclohexylamine salt with a melting point of 159 to 161 ^° C. immediately crystallizes out.

Example 45 1- (4-Mercaptobutanol) -L-proline

1.08 g of 1- (4-benzylthiobutanoyl) -L-proline are in a Mixture of 4 ml of water and 2.7 ml of concentrated ammonia dissolved. The resulting mixture is 1 hour at room temperature stirred, then diluted with water and filtered off. The filtrate is extracted with ethyl acetate and the aqueous Phase is evaporated under reduced pressure. Thereafter, the obtained ammonium salt of 1- (4-mercaptobutanoyl) -L-proline becomes by ion exchange chromatography on a Diethylaminoethyl Sephadex (crosslinked dextran) column with

709833/1005

MO

Purified with an ammonium bicarbonate gradient. Yield: 0.7 g · The ammonium salt obtained is then dissolved in 2 ml of water and passed through a cation exchanger in the H ⁺ form. The resulting free acid is eluted with water. The product-containing fractions (positive sulfhydryl and carboxyl detection) are collected and freeze-dried. The title compound is obtained. According to Example 44, the dicyclohexylammonium salt with a melting point of 157 to 58 ° C. is prepared therefrom.

Example 46
4-bromo-2-methylbutyric acid

1.4 g of ethyl-4-bromo-2-methylbutanoate (prepared according to G. Jones and J. Wood, Tetrahedron Letters, Vol. 21, (1965), p 2961) are dissolved in 50 ml of methylene chloride at -10 ⁰ C. and 50 ml of a 1 molar solution of boron tribromide in methylene chloride are added dropwise with stirring. The mixture obtained is then stirred for 1 hour at -10 ° C. and for 2 hours at room temperature. The reaction is then ended by careful addition of water. The layers are separated, the organic phase is washed with water, dried and evaporated. The title compound is obtained.

Example 47

1- (4-B: enzoylthio-2-methylbutanoyl) -L-proline

a) A mixture of 8 g of 4-bromo-2-methylbutyric acid and

7 g of thionyl chloride is stirred for 16 hours at room temperature, then evaporated to dryness and under reduced pressure Distilled pressure.

b) A solution of 2.88 g of L-proline in 25 ml of 1 η sodium hydroxide solution is cooled in an ice bath and treated with 12.5 ml of 2 η sodium hydroxide solution and 3.9 g of the 4-bromo-2-methylbutter-

acid chloride added. The resulting mixture is stirred for 3 1/2 hours at room temperature and then with

709833/1005 ^J.

a suspension of 3.75 g of thiobenzoic acid and 2.4 g of potassium carbonate added in 25 ml of water. The mixture is then stirred for about 15 hours, then with concentrated Acidified hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained is on a silica gel column with a mixture chromatographed of benzene and acetic acid in a volume ratio of 7 i 1. The fractions containing the product v / earth collected and evaporated to dryness under reduced pressure. The title compound is obtained.

Example 48

1- (4-Mercapto ~ 2-methylbutanoyl) -L-proline

Example 45 is repeated with the change that, instead of 1- (4-benzoylthiobutanoyl) -L-proline, 1- (4-benzoylthio-2-methylbutanoyl) -L-proline is used. The title compound is obtained.

Example 49

4-bromo-2-benzyl butyric acid

Example 46 is repeated with the change that instead of ethyl 4-bromo-2-methylbutanoate, ethyl 4-bromo-2-benzylbutanoate (prepared according to G. Jones and J. Wood, Tetrahedron Letters, Vol. 21, (1965), p. 2961 with diethyl benzyl alonate as starting compound) is used. It the title compound is obtained.

Example 50 1- (4-Benzovlthio-2-benzylbutanovl) -L - proline

Example 47 is repeated with the change that 4-bromo-2-benzylbutyric acid instead of 4-bromo-2-methylbutyric acid is used. The title compound is obtained.

709833/1005

Example 51
1- (4-Mercapto-2-benzylbutanoyl) -L-proline

Example 45 is repeated with the change that, instead of 1- (4-benzoylthiobutanoyl) -L-proline, 1- (4-benzoylthio-2benzyl butanoyl) -L-proline is used. The title compound is obtained.

Example 52
1- (4-mercaptobutanoyl) -L-hydroxyproline

Example 44 is repeated with the change that instead of

the
of L-proline (^ - hydroxyproline is used. The 1- (4-benzoylthiobutanoyl) -L-hydroxyproline obtained is then subjected to ammonolysis according to Example 45. The title compound is obtained.

Example 53
1- (4-mercaptobutanoyl) -L-azetidine-2-carboxylic acid

Example 44 is repeated with the change that instead of of L-proline, the L-azetidine-2-carboxylic acid is used. The obtained 1- (4-benzoylthiobutanoyl) -L-azetidine-2-carboxylic acid is then subjected to ammonolysis according to Example 45. The title compound is obtained.

Example 54
1- (4-mercaptobutanoyl) -L-piperidine-2-carboxylic acid

Example 44 is repeated with the change that L-piperidine-2-carboxylic acid is used instead of L-proline. The 1- (4-benzoylthiobutanoyl) -L-piperidine-2-carboxylic acid obtained is then subjected to ammonolysis according to Example 45 subjected. The title compound is obtained.

Example 55
1- (3-Acetylthiobutanoyl) -L-proline tert-butyl ester

A solution of 5.1 g of L-proline tert-butyl ester in 60 ml Methylene chloride is cooled in an ice bath and with stirring

709833/1005

6.2 g dicyclohexylcarbodiimide and 4.86 g 3-acetylthiobutyric acid offset. After 15 minutes the ice bath is removed and the mixture is stirred for 16 hours at room temperature. The resulting precipitate is filtered off, the filtrate evaporated to dryness and the residue on a Chromatographed silica gel column with chloroform as the eluent. Yield: 5.2 g of the title compound.

Example 56 1- (3-Acetylthiobutanoyl) -L-proline

5.2 g of the 1- (3-acetylthiobutanoyl) -L-proline tert-butyl ester prepared according to Example 55 are dissolved in a mixture of 60 ml of trifluoroacetic acid and 30 ml of anisole and stored for 1 hour at room temperature. Afterward the solvents are distilled off under reduced pressure and the residue several times from a Mixture of diethyl ether and hexane precipitates. Yield: 4 g of the title compound. According to Example 44 is the dicyclohexylamine salt from 175 to 176 ° C.

Example 57 1- (3-Mercaptobutanol) -L-proline

0.86 g of the 1- (3-acetylthiobutanoy]) - L-proline prepared according to Example 56 are dissolved in 20 ml of a 5.5 μm solution of ammonia in methanol. The resulting mixture is stored for 2 hours at room temperature, then the solvent is distilled off under reduced pressure and the residue is chromatographed on an ion exchanger with water as the mobile phase. The product-containing fractions are collected and freeze-dried. Yield: 0.6 g of the title compound. According to Example 44, the dicyclohexylamine salt with a melting point of ^{183 to 184 ° C. is produced therefrom.}

709833/1005

Example 58
1- / 3- (ethoxycarbonyl) -thiopropanovl / -L-proline

A solution of 2.03 g of 3-mercaptopropanoyl-L-proline in 30 ml of 1 η sodium bicarbonate ver1setzt with 1.2g Chloraraeisensäurl ^»ye. The resulting mixture is vigorously stirred for 1 hour at 5 ° C. and then for 2 hours at room temperature. The reaction mixture is then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water / water, dried over magnesium sulfate and evaporated to dryness. The title compound is obtained.

Example 59 1- / 3- (ethoxythiocarbonyl) -thj.opro "panoyl / - L-proline

A solution of 5.75 g of L-proline in 50 ml of 1 η sodium hydroxide solution is cooled in an ice bath and 25 ml of 2 η sodium hydroxide solution and 8.5 g of 3-bromopropionyl chloride are added while stirring. After 5 minutes the ice bath is removed, the mixture is stirred at room temperature for 3 hours and then 9.6 g of potassium ethyl xanthate are added. The mixture obtained is then stirred for about 15 hours at room temperature, then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is evaporated to dryness and the residue is chromatographed on a silica gel column with a mixture of benzene and acetic acid in a volume ratio of 7 ί 1 as the mobile phase. The title compound with a melting point of 94 to 95 ^° C. is obtained.

Example 60
1- / 3- (benzylthiocarbonyl) -thiopropanoyl / -L-proline

A solution of 1.6 g of 1- (3-mercaptopropanoyl) -L-proline in 24 ml of 1 η sodium bicarbonate solution is cooled in an ice bath and a solution of 11 ml of benzoylthiocarbonyl chloride in 20 ml of dioxane is added in 5 portions in 30 minutes. Thereafter the ice bath is removed and the resulting mixture

709833/1005

Stirred for 2.5 hours at room temperature. The reaction mixture is then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate and evaporated to dryness. The title compound is obtained.

Example 61 1 - /? - (Ethylthiothiocarbonyl) -thiopropanov17-L-proline

A solution of 5.75 g of L-proline in 50 ml of 1 η sodium hydroxide solution is cooled in an ice bath and mixed with 25 ml of 2 η sodium hydroxide solution and 8.5 g of 3-bromopropionyl chloride while stirring. After 5 minutes the ice bath is removed, the mixture is stirred for 3 hours at room temperature and then with 10.5 g of potassium ethyl trithiocarbonate added. The mixture is then stirred at room temperature for about 15 hours, then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is made over magnesium sulfate dried and evaporated to dryness. The title compound is obtained.

Example 62 3- (Methylaminothiocarbonyl) thiopropionic acid

A solution of 5.3 g of 3-mercaptopropionic acid in a mixture of 250 ml of pyridine and 100 ml of 0.5 μm sodium hydroxide solution is mixed with 4 g of methyl isothiocyanate. The mixture obtained is ^{heated to 40 °} C. for 2 hours and then evaporated to dryness under reduced pressure. The residue obtained is dissolved in 100 ml of water, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The diethyl ether extract is then evaporated to dryness. The title compound with a melting point of 36 ° to 87 ° C. is obtained.

709833/1005

.kr.

Example 63

1 - / ^ - (Methylaminothiocarbonvl) -thiopropanovlZ-L-prolintert.-butyl ester

A solution of 1.71 g of L-proline tert-butyl ester and 1.35 g of hydroxybenzotriazole in 10 ml of methylene chloride is cooled in an ice bath and, while stirring, 2.06 g of dicyclohexylcarbodiimide and 1.79 g of 3- (methylaminothiocarbonyl) thiopropionic acid are added. After 15 minutes the ice bath is removed and the mixture is stirred for about 15 hours. The resulting precipitate is then filtered off, the filtrate is diluted with ethyl acetate and ashed until a neutral reaction occurs. The ethyl acetate layer is separated and evaporated to dryness. The title compound with a melting point of 129 to 130 ^° C. is obtained.

Example 64 1- / 3- (Methylaminothiocarbonyl) -thiopropanoyl7-L-proline

A) 0.98 g of 1- / 3- (Methylaaiinothiocarlionyl) -thiopropanoyl7-L-proline tert-butyl ester v / earth dissolved in a mixture of 3.6 ml of anisole and 7.5 ml of trifluoroacetic acid. The mixture is kept at room temperature for 1 hour and then evaporated to dryness. The residue obtained is reprecipitated three times from a mixture of diethyl ether and hexane and then on a silica gel column with a mixture of benzene and acetic acid in a volume ratio 75 i 25 chromatographed as an eluent. It becomes the title compound obtained, R ^ = 0.4 (silica gel, benzene / acetic acid 75:25). The dicyclohexylammonium salt has the F. 127 bis 129 ° C.

B) A solution of 10.1 g of 3-mercaptopropanoyl-L-proline in a mixture of 250 ml of pyridine and 100 ml of 0.5 η sodium hydroxide solution is mixed with 4 g of methyl isothiocyanate. The mixture obtained is ^{heated to 40 °} C. for 2 hours and then evaporated to dryness under reduced pressure. The residue is then dissolved in 100 ml of water, with

709833/1005

acidified ter hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is then evaporated to dryness. The title compound is obtained.

Example 65 1 - /? - (Ethylaminocarbonvl) -thiopropanovl7-L-prolln

A solution of 1 g of 1- (3-mercaptopropanoyl) -L-proline in a mixture of 5 ml of 1 η sodium hydroxide solution and 5 ml of pyridine is mixed with 0.45 ml of ethyl isocyanate. The mixture obtained is ^{heated to 40 °} C. for 4 hours and then evaporated under reduced pressure. The residue is then extracted with 0.1 η hydrochloric acid and ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and evaporated to dryness. The title compound is obtained. The dicyclohexylammonium salt, melting at 150 to 152 ⁰ C is obtained by reacting a solution of the free acid in ethyl acetate with dicyclohexylamine.

Example 66 1- / 3- (Ethoxycarbonyl) -thio-2-methylpropanov17-L-proline

Example 58 is repeated with the change that, instead of 3-mercaptopropanoyl-L-proline, 1- (3-mercapto-2-methylpropanoyl) -L-proline is used. The title compound is obtained.

Example 67 1- / 3- (Ethoxycarbonyl) -thiobutanoov17-L-proline

Example 58 is repeated with the change that, instead of 3-mercaptopropanoyl-L-proline, 1- (3-mercaptobutanoy3.) -L-proline is used. The title compound is obtained.

709833/1005

Example 68

1- / 3- (Ethoxythiocarbonyl) -thiopropanov17-L-azetidine-2-carboxylic acid

Example 59 is repeated with the change that L-azetidine-2-carboxylic acid is used instead of L-proline. The title compound is obtained.

Example 69

1- / 3- (Ethoxylthiocarbonvl) -thj.opro-panoyl7-L-piperidine-2-carboxylic acid

Example 59 is repeated with the change that L-piperidine-2-carboxylic acid is used instead of L-proline. The title compound is obtained.

Example 70 1-A- (Benzyl th.iocarbonyl) -thiobutanoov17-L-proline

Example 60 is repeated with the change that A-mercaptobutanoyl-L-proline instead of 3-mercaptopropanoyl-L-proline is used. The title compound is obtained.

Example 71 1-72- (Benzylthiocarbonyl) -thiopropanoyl7-L-proline

Example 60 is repeated with the change that instead of 3-mercaptopropanoyl-L-proline, 2-mercaptopropanoyl-L-proline is used. The title compound is obtained.

Example 72

1- / 3- (ethylthiothiocarbonyl) thiopropanov17-L-proline methyl ester

A solution of 1- / 3- (ethylthiothiocarbonyl) -thiopropanoyl / -L-proline in ethyl acetate v / ird up to a permanent yellow color with a solution of diazomethane in diethyl ether.

J 7 09833/1005

acts. After that, add a few drops of acetic acid to the mixture added until the yellow color disappears, and the solvents are distilled off under reduced pressure. The title compound is obtained.

Example 73

1 - / 3- (Methylapiinothiocarbonyl) -thiopropanoyl7-5-hydroxy-L-piperidine-2-carboxylic acid

Example 64, method B, is repeated with the change that, instead of 3-mercaptopropanoyl-L-proline, 1- (3-mercaptopropanoyl) -5-hydroxy-L-piperidine-2-carboxylic acid is used. The title compound is obtained.

Example 74

1- / 3- (methylaminothiocarbonyl) -thio-2-methylpropanovl / -L-proline amide

Example 64, Procedure B, is repeated with the change, that instead of 3-mercaptopropanoyl-L-proline, 1- (3-mercapto-2-methylpropanoyl) -L-proline amide is used. The title compound is obtained.

Example 75 1- / 3- (Phenoxycarbonyl) -thiopropanoyl AL-proline

Example 58 is repeated with the change that instead of of ethyl chloroformate and phenyl chloroformate is used. The title compound is obtained.

Example 76 1 - / ^ - (Phenoxycarbonyl) -thiobutanovl / -L-proline Example 58 is repeated with the change that instead of ethyl chloroformate ^^ phenyl chloroformate and instead of 3-mercaptopropanoyl-L-proline, 4-mercaptobutanoyl-L-proline is used. The title compound is obtained.

709833/1005

Example 77 1- / 3- (Phenylaminocarbonyl) -thiopropanov17-L-proline

Example 65 is repeated with the change that instead of of ethyl isocyanate pnenyl isocyanate is used. The title compound is obtained.

Example 78 1- / 3- (Phenethylaminocarbonyl) -thiopropanovl / -L-proline

Example 65 is repeated with the change that phenethyl isocyanate is used instead of ethyl isocyanate. It the title compound is obtained.

Example 79

1- / 3- (Ethylaminocarbonyl) -thio-2-benzylpropanoyl7-L-proline

Example 65 is repeated with the change that, instead of 1- (3-mercaptopropanoyl) -L-proline, 1- (3-mercapto-2-benzylpropanoyl) -L-proline is used. The title compound is obtained.

Example 80 1- (3-methylthiopropanoyl) -L-proline

A) 51 g of 3-MethylthiopropionsäureHGthylester v / ground 30 minutes hydrolyzed at 100 ⁰ C with I50 ml lOprozentiger sodium hydroxide solution. The solution is then cooled, extracted with diethyl ether and then acidified. The crude acid obtained is distilled and converted into the acid chloride with thionyl chloride.

A solution of 11.5 g of L-proline in 100 ml of 1 η sodium hydroxide solution is cooled in an ice bath and added dropwise with vigorous stirring in 10 minutes with 6.9 g of 3-methylthiopropionic acid chloride offset. After 5 hours the reaction mixture is acidified and extracted with diethyl ether. The title compound is obtained. For the production of the dicyclohexylammonium salt from the F. I69 to 171 ° C is a solution of

709833/1005

free acid in ethyl acetate mixed with dicyclohexylamine.

B) A solution of 115 g of 1- (3-mercaptopropanoyl) -L-proline ethyl ester and 11.5g sodium in 400 ml ethanol is with 71 g of methyl iodide were added. The resulting mixture is about Left to stand for 15 hours, then the ethanol is distilled off under reduced pressure and the residue in a mixture dissolved by ethyl acetate and water. The organic layer is then separated, dried and reduced under reduced pressure Pressure evaporated to dryness. 98 g of 1- (3-methylthiopropanoyl) -L-proline ethyl ester are grounded obtained, which is suspended in a mixture of 200 ml of methanol and 200 ml of 5 η sodium hydroxide solution and stirred at room temperature for 5 hours. The methanol is then distilled off under reduced pressure, the aqueous phase extracted with ethyl acetate, acidified and extracted again with ethyl acetate. This The last ethyl acetate extract is washed with water, dried and evaporated to dryness. It becomes the title compound obtain.

Example 81 1- / 3- (4-chlorophenvl) -thiopropanovl / -LT) rolin

A solution of 5.75 g of L-proline in 50 ml of 1 η sodium hydroxide solution is used cooled in an ice bath and mixed with 25 ml of 2 η sodium hydroxide solution and 8.5 g of 3-bromopropionyl chloride while stirring. After 5 minutes the ice bath is removed and the mixture for 3 hours at room temperature touched. The reaction mixture is then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated to dryness under reduced pressure. Thereafter, the residue obtained is in a mixture of 8 g of 4-chlorobenzenethiol, 4.2 g of sodium hydroxide and 300 ml of ethanol dissolved. The solution obtained is refluxed for 6 hours. Then the solvent distilled off under reduced pressure, the residue dissolved in water, acidified with concentrated hydrochloric acid and with Ethyl acetate extracted. The ethyl acetate extract is treated with water

709833/1005

water washed, dried and evaporated to dryness under reduced pressure. The title compound is obtained.

Example 82 1- / 3- (Benzylthiomethyl) thiopropanoyl7-L-proline

8 »1 g 1- (3-mercaptopropanoyl) -L-proline v / earth in 100 ml boiling, dissolved in liquid ammonia and mixed with small pieces of sodium until it remains blue. Thereafter a little ammonium chloride is added until the blue color disappears. 6.9 g of benzylthiomethyl chloride are then added to the resulting mixture and the ammonia is evaporated. The last traces of ammonia are distilled off under reduced pressure. The residue obtained is dissolved in water dissolved and extracted with ethyl acetate. The aqueous phase is then acidified with concentrated hydrochloric acid and with Ethyl acetate extracted. The ethyl acetate extract is washed with water, dried and evaporated to dryness. It the title compound is obtained.

Example 83 1- / 3- (Acetamidomethvl) -thiopropanoyl7-L-proline

2 g of 1- (3-mercaptopropanoyl) -L-proline and 0.89 g of N-hydroxymethylacetamide are dissolved in 10 ml of trifluoroacetic acid and stored at room temperature for 1 hour. The excess trifluoroacetic acid is then distilled off under reduced pressure and the residue is reprecipitated several times from a mixture of diethyl ether and hexane. Finally the residue is extracted by shaking with a mixture of dilute hydrochloric acid and ethyl acetate. The organic layer is washed with water, dried and evaporated to dryness. The title compound is obtained.

709833/1005

Example 84 1- (methylthioacetyl) -L-proline

Example 80, method A, is repeated with the change that instead of ethyl 3-methylthiopropionate, methyl methylthioacetate is used. The title compound of F. 123 Ms 124 ⁰ C is obtained.

Example 85

1- (Benzylthioacetyl) -L-proline

Example 80, method A, is repeated with the change that the benzylthioacetyl chloride is used instead of 3-methylthiopropanoyl chloride. The title compound with a melting point of 86 to 88 ^° C. is obtained.

Example 86 1- / 3- (2-Phenylethyl) -thiopropanoyl / -L-proline

Example 80, Procedure B, is repeated with the change, that phenethyl bromide is used instead of methyl iodide. The title compound is obtained.

Example 87 1 - / 3- (Triphenylmethyl) -thiopropanovl / ~ L-proline

Example 80, Procedure B, is repeated with the change,

the

that triphenylmethyl chloride used instead of methyl iodide will. The title compound is obtained.

Example 88 1- (3-methylthio-2-methvlpropanovl) -L-proline-amide

Example 80, method B, is repeated with the change that instead of the 1- (3-mercaptopropanoyl) -L-proline ethyl ester the 1- (3-mercapto-2-methylpropanoyl) -L-proline amide is used. Excluding that set out in Example 80, Procedure B Hydrolysis gives the title compound.

709833/100 5

Example 89

1- (3-Methylthiopropanovl) -L-azetidine-2-carboxylic acid

Example 80, method A, is repeated with the change that L-azetidine-2-carboxylic acid is used instead of L-proline will. The title compound is obtained.

Example 90 1- / 3- (4-methoxyphenyl) -thiopropanoyl7-L-proline

Example 81 is repeated with the change that 4-methoxybenzenethiol is used instead of 4-chlorobenzenethiol will. The title compound is obtained.

Example 91 1- (3-Methylthiopropanoyl) -L-piperidine-2-carboxylic acid

Example 80, method A, is repeated with the change that instead of L-proline, L-piperidine-2-carboxylic acid is used. The title compound is obtained.

Example 92 1- / 2- (4-chlorophenyl) -thiopropanovl / -L-proline Example 81 is repeated with the change that 2-bromopropionyl chloride is used instead of 3-bromopropionyl chloride. The title compound is obtained.

Example 93 1- / | 5- (Diphenylmethyl) -thio-2-benzylpropanovl7-L-proline 0.92 g diphenylmethanol and 1.5 g 1- (3-mercepto-2-benzylpropanoyl) -L-proline are dissolved in 10 ml trifluoroacetic acid and 30 minutes at room temperature kept. The excess trifluoroacetic acid is then distilled off under reduced pressure. The title compound is obtained.

709833/1005

Example 94 1- / 4- (4 ^ -Chlorophenyl) -thiobutano yl7-L-proline

Example 81 is repeated with the change that instead of of 3-bromopropionyl chloride used the 4-bromopropionyl chloride will. The title connection will be retained.

Example 95 1- / 3- (Benzylthiomethyl j-thiobutanoyiy-L-'prolln

Example 82 is repeated with the change that instead of 3-mercaptopropsnoyi-L-proline, 3-mercaptobutanoyl-L-proline is used. The title compound is obtained.

Example 96

1-A- (Acetamidonethvl) -thio-2-methylbutanoyl7-L-proline

Example 83 is repeated with the change that, instead of 1- (3-mercaptopropanoyl) -L-proline, 1- (4-mercapto-2-methylbutanoyl) -L-proline is used. The title compound is obtained.

Example 97 1- / 3- (ethyldithio) - pro-panoyl7-L - proline

A) A solution of 8.4 g of ethyl thiosulfinate in 100 ml of methanol 10 g of 3-mercaptopropanoyl-L-proline are added. The resulting mixture is 4 hours at room temperature strongly stirred. The methanol is then distilled off under reduced pressure. The title compound is obtained.

B) A solution of 10 g of 3-mercaptopropanoyl-L-proline in water is kept at a pH of 6 to 7 by careful addition of sodium hydroxide and mixed with a solution of 8.4 g of ethyl thiosulfinate in 50 ml of ethanol. The mixture obtained is vigorously stirred at room temperature until the thiol groups react negatively. The reaction mixture is then diluted with water, adjusted to pH 8 and extracted with ethyl acetate. Then will

J 709833/1005

the aqueous phase acidified to pH 3 and extracted again with ethyl acetate. The latter ethyl acetate extract is washed with water, dried and evaporated to dryness. The title compound is obtained.

Example 98 1- / 3- (4-Metholphenyl) -dithiopropanov17-L-proline

A solution of 2 g of 3-mercaptopropanoyl-L-proline in 20 ml 0.5 η sodium hydroxide solution is cooled in an ice bath and mixed with a solution of 1.76 g of 4-methylphenylsulfenyl chloride in 20 ml of diethyl ether offset. The resulting mixture is vigorously stirred for 1 hour. The aqueous phase is then separated off with concentrated Acidified hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and dried and evaporated to dryness. The title compound is obtained.

Example 99 1- (3-Phenyldithiopropanoyl) -L-proline

Example 97 is repeated with the change that instead of of ethyl thiosulfinate I phenyl thiosulfinate (made from Phenyl disulfide according to U. Weber and P, Hartter, Z. Physiol. Chem., Vol. 351, (1970), p. 1384) is used. The title compound is obtained.

Example 100 1- / 3- (2-phenylethyl) -dithiopropanoyl7-L-proline

Example 97 is repeated except that instead of

for Q C

of ethyl thiosulfinate 2-phenylethylthiosulfinate (manufactured from phenethyl disulfide) is used. The title compound is obtained.

709833/1005

Example 101 1 - / 3- (2-Hydroxyethyl) -dithiopropanoyl_7-L-proline

A solution of 21 g of 1,1 '- / "(sulfinylthio) -bis- (3-propanoyl) _ / - bis-L-proline 4.2 g of mercaptoethanol are added to 100 ml of methanol. The mixture obtained is for 4 hours Vigorously stirred at room temperature. Thereafter, the methanol is distilled off under reduced pressure and the residue on a Silica gel column purified by chromatography. It becomes the title compound obtain.

Example 102 1- (2- £ thvldithiopropanovl) -L-proline

Example 97 is repeated with the change that instead of 3-mercaptopropanoyl-L-proline, 2-mercaptopropanoyl-L-proline is used. The title compound is obtained.

Example 103 1- / 3- (4-methylphenyl) -dithiobutanoyiy-L-proline

Example 98 is repeated with the change that instead of 3-mercaptopropanoyl-L-proline, 3-mercaptobutanoyl-L-proline used v / ird. The title compound is obtained.

Example 104 1- (3-Ethyldithio-2-methylpropanovl) -L-proline methyl ester

Example 97 is repeated with the change that, instead of 3-mercaptopropanoyl-L-proline, 1- (3-mercapto-2-methylpropanoyl) -L-proline is used. The product obtained is then v / ird according to Example 72 with a solution of diazomethane treated in diethyl ether. The title compound is obtained.

709833/1005

Example 105 1- · (3-Ethyldithiopropanoyl) -L-azetidine-2-carboxylic acid Example 97 is repeated with the change that 3-mercaptopropanoyl-L-azetidine-2-carboxylic acid is used instead of 3-mercaptopropanoyl-L-proline will. The title compound is obtained.

Example 106

1- / 3- (4-methylphenyl) -dithio-2-methylpropanoyl7-L-hydroxyproline

Example 98 is repeated with the change that instead of 3-mercaptopropanoyl-L-proline, 1- (3-mercapto-2-methylpropanoyl) -L-hydroxyproline is used. The title compound is obtained.

Example 107

1- (4-ethyldithiobutanoyl) -L-oiperidine-2-carboxylic acid

Example 97 is repeated with the change that, instead of 3-mercaptopropanoyl-L-proline, 4-mercaptobutanoyl-L-piperidine-2-carboxylic acid is used. The title compound is obtained.

Example 108

1- (3-Ethyldithiopropanoyl) -5-hydroxv-L-piperidine-2-carboxylic acid

Example 97 is repeated with the change that, instead of 3-mercaptopropanol-L-proline, 1- (3-mercaptopropanoyl) -5-hydroxy-L-piperidine-2-carboxylic acid is used. The title compound is obtained.

Example 109 1- / 3- (2-Anino-2-carboxyethyl) -dithiopropanoyl7-L-proline

A 0.5 molar solution of dirhodane in glacial acetic acid is made by shaking 600 mg of dry lead thiocyanate for 10 minutes with a solution of 75 / ü. Bromine in 3 ml of glacial acetic acid in one

709833/1005

sealed vessel made. The resulting lead bromide

will lead thiocyanate and excess ι separated by centrifugation. Then 2.5 ml of the solution obtained are mixed with 2.5 ml of a 0.41 molar solution of cysteine hydrochloride which has been neutralized beforehand with dilute sodium hydroxide solution. The mixture obtained is immediately added to 0.75 ml of a 1.9 molar solution of 3-mercaptopropanoyl-L-proline neutralized beforehand with dilute sodium hydroxide solution. After 20 minutes, the reaction mixture is titrated with a solution of iodine in ethanol until it turns brown and adjusted to pH 3. The resulting precipitate is then filtered off and the filtrate is passed through a cation exchanger. The ion exchange column is washed with water until the eluate shows a neutral reaction and then further eluted with a pyridine-acetate buffer mixture of pH 6.0. The fractions containing the disulfide of cysteine and the 3-mercaptopropanoyl-L-proline are collected and evaporated to dryness.

Example 110 1.1 '- / Dithiobis- (3-pro-panovl) 7-bis-L-proline

0.95 g of 3-mercaptopropanoyl-L-proline are dissolved in 20 ml of water and the solution is adjusted to a pH of 6.5 with 1 n sodium hydroxide solution. A solution of iodine in ethanol is then added dropwise to the solution, the pH being kept at 6.5 by careful addition of 1 n sodium hydroxide solution. As soon as a permanent yellow color is achieved, the addition of iodine is interrupted and the solution is decolorized by a small amount of sodium thiosulphate. The reaction mixture is then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated to dryness. The title compound is obtained. The dicyclohexylammonium salt with a melting point of 179 to 180 ^° C. is produced by adding dicyclohexylamine to a solution of the free acid in acetonitrile.

70983 3/1ODS

Example 111 1.1 ^l - / Dithiobis- (2-D-methyl-3-propanovl) / - bis-L-proline

Example 110 is repeated with the change that 3-mercapto-2-D-methylpropanoyl-L-proline is used instead of 3-mcapto-propanoyl-L-proline. The title compound with a melting point of 236 to 237 ^° C. is obtained.

Example 112 1,1 '- / Dith.iobis- (2-propanoyl JT-bis-L-proline

Example 110 is repeated with the change that instead of 3-mercaptopropanoyl-L-proline, 2-mercaptopropanoyl-L-proline is used. The title compound is obtained.

Example 113 1,1 '- (Dithiobisacetyl) -bis-L-hydroxyproline

Example 110 is repeated with the change that instead of of 3-mercaptopropionyl-L-proline, 1- (2-mercaptoacetyl) -L-hydroxyproline is used. The title compound is obtained.

Example 114 1,1 '- (DithiobisacetylJ-bis-L-azetidine-g-carboxylic acid

Example 110 is repeated with the change that instead of 3-mercaptopropanoyl-L-proline, 1- (2-mercaptoacetyl) -L-azetidine-2-carboxylic acid is used. The title compound is obtained.

Example 115 1,1 '- / pithiobis (3-propanoyl) / - bis-L-piperidine-2-carboxylic acid

Example 110 is repeated with the change that 3-mercaptopropanoyl-L-piperidine-2-carboxylic acid is used instead of 3-mercaptopropanoyl-L-proline is used. The title compound is obtained.

709833/1005

Example 116 1.1 ^t - / bithiobis (3-propanoyl) 7-bis-4-methvl-L-proline

Example 110 is repeated with the change that, instead of 3-mercaptopropanoyl-l-proline, 1- (3-mercaptopropanoyl) -4-methyl-L-proline is used. The title compound is obtained.

Example 117

1.1 '- / Dithiobis- (3-propanovl) 7-bis-5-hydroxy-L-piperidine-2-carboxylic acid

Example 110 is repeated with the change that instead of of 3-mercaptopropanoyl-L-proline the 1- (3-mercaptopropanoyl) -5-hydroxy-L-piperidine-2-carboxylic acid is used. The title compound is obtained.

Example 118 1,1 '- / dithiobis (2-benzyl-3-propanovl) 7-bis-L-proline

Example 110 is repeated with the change that instead of 3-mercaptopropanoyl-L-proline, 1- (3-mercapto-2-benzylpropanoyl) -L-proline is used. The title compound is obtained.

Example 119

1.1 * - / bithiobis- (2-methyl-3-propanovl) / - bis-L-piperidine-2-carboxylic acid

Example 110 is repeated with the change that, instead of 3-mercaptopropanoyl-L-proline, 1- (3-mercapto-2-methylpropanoyl) -L-piperidine-2-carboxylic acid is used. The title compound is obtained.

At s. Piel 120 1,1 '- / dithiobis (4-butanovl) 7-bis-L-proline

Example 110 is repeated with the change that instead of 3-mercaptopropanoyl-L-proline the 4-mercaptobutanoyl-L-

J 709833/1005

Proline is used. The title compound is obtained.

Example 121 1,1 '- / Oithiobis- (2-benzyl-4-butanoyl) 7-bis-L-proline

Example 110 is repeated with the change that instead of 3-mercaptopropanoyl-L-proline, 1- (4-mercapto-2-benzylbutanoyl) -L-proline used v / ird. Eo will obtain the title compound.

Example 122 1,1 '- / Oithiobis- (3-butanoyl) / - bis-L-proline

Example 110 is repeated with the change that instead of 3-mercaptobutanoyl-L-proline is used by 3-mercaptopropanoyl-L-proline. The title compound is obtained.

Example 123 1,1 '- / Oithiobis (3-propanoyl) 7-bis-L-proline methyl ester

A solution of 1,1 '- / Oithiobis- (3-propanoyl) _ / - bis-L-proline in methanol is treated with a solution of diazomethane in diethyl ether until it remains yellow. That The resulting mixture is added with a few drops after 15 minutes Acetic acid added. The solvents are then distilled off under reduced pressure. It becomes the title compound obtain.

Example 124 1,1 '- / Oithiobis- (3-propanoyl) 7-bis-L-proline-amide

A solution of 1,1 · - / Oithiobis- (3-propanoyl 17-bis-L-proline methyl ester ammonia is saturated in methanol with cooling in an ice-water bath. The mixture is then at for 16 hours Stored in a pressure vessel at room temperature. The solvents are then distilled off under reduced pressure. The title compound is obtained.

709833/10 OS

Example 125 1.1 '- / bithiobis- (2-phenyl-3-propanovl) y-bis-L-proline

Example 110 is repeated with the change that, instead of 3-mercaptopropanoyl-L-proline, 1- (3-mercapto-2-phenylpropanoyl) -L-proline is used. The title compound is obtained.

Example 126 1.1 '- / 7SuIfJnVItMo) -Ms- (3-propanovl) / - bis-L-proline

A solution of 40 g 1,1 '- / dithiobis- (3-propanoyl / -bis-L-proline 0.12 mol of peroxyacetic acid is added to 500 ml of glacial acetic acid while stirring and cooling in an ice bath. The received Mixture is kept at room temperature for about 15 hours. The solvent is then distilled off under reduced pressure. The title compound is obtained.

Example 127 1.1 * -f ( sulfonyl thio) -bis- (3-propanovl) 7-bls-L-proline A solution of 4 g 1,1 '- / Oithiobis- (3-propanoylX7-bis-L-proline in 80 2.0 ml of a 30 percent strength hydrogen peroxide solution are added to ml of glacial acetic acid, the solution is then stored for 30 hours at room temperature, after which the solvent is distilled off under reduced pressure to give the title compound.

Example 128 1.1 ^l - / YSulfinvlthio) -bis- (2-propanovl) 7-bis-L-prolln

Example 126 is repeated except that instead of from 1,1 '- / dithiobis- (3-propanoyl) 7-bis-L-proline to 1,1 · - / dithiobis- (2-propanoyl-7-bis-L-proline is used. The title compound is obtained.

709833/1005

Example 129 1,1 '- / (Sulfinvlthio) -bisacetv17-bis-L-azetidine-2-carboxylic acid

Example 126 is repeated with the change that instead of 1,1 '- / dithiobis- (3-propanoyl17-bis-L-proline the 1,1 '- (Dithiobisacetyl) -bis-L-azetidine-2-carboxylic acid used will. The title compound is obtained.

Example 130 1,1 '- / TSulfirivlthio) -bls- (3-r> roTjanovl) / - bis-4-methvl-L-proli n

Example 126 is repeated with the change that instead of 1,1 '- / dithiobis- (3-propanoyl17-bis-L-proline the 1,1 '- / Oithiobis- (3-propanoyl) / - bis-4-methyl-L-proline used will. The title compound is obtained.

Example 131

1.1 '- / TSulfinvlthio) -bis - (2-benzyl-3-propanovl) 7-bis-L-proline

Example 126 is repeated with the change that instead of 1,1 '- / dithiobis- (3-propanoyl) / - bis-L-proline the 1,1 '- / dithiobis- (2-benzyl-3-propanoyl} / - bis-L-proline used will. The title compound is obtained.

Example 132 1.1 '- / (sulfinylthio) -bis- (4-butanovl) 7-bis-L-proline

Example 126 is repeated with the change v / that instead of of 1,1 · - / Oithiobis- (3-propanoyl) 7-kis-L-proline das 1 »1 '- / dithiobis (4-butanoyl) 7-bis-L-proline is used. The title compound is obtained.

Example 133 1,1 '- / (SuIf inylthio) -bis- (3-butanoyl) 7-bis-L-proline

Example 126 is repeated with the change that instead of 1,1'-ZÖithiobis- (3-propanoyl) 7-bis-L-proline the 1,1'-ZÖithiobis- (3-butanoylL / -bis-L-proline is used. The title compound is obtained. _l

709833 / 100S

Example 134 1,1 '- / TSulfinvlthio) -bis- (2-ethyl-3-propanovl7-bls-L-proline

Example 126 is repeated with the change that instead of 1,1 '- / dithiobis- (3-propanoyl) .7-bis-L-proline the 1,1 '- / Dithiobis- (2-methyl-3-propanoyl) _7-bis-L-proline are used will. The title compound is obtained.

Example 135 1.1 ^t - / TSulfinylthio) -bis- (2-phenvl-3-propanoyll7-bis-L-proline

Example 126 is repeated with the change that instead of 1,1 '- / dithiobis- (3-propanoyl / -bis-L-proline the 1,1 '- / Dithiobis- (2-phenyl-3-propanoyl) 7-bis-L-proline are used will. The title connection will be maintained.

Example 136

1- (3 - // 3- (2-carboxy-1-pvrrolidinvl) -3-oxopror> vl7-dithio? -2-methvlpropanoyl) -L-proline

Example 97 is repeated with the change that instead of of ethyl thiosulfinate 1,1 '- / (sulfinylthio) -bis- (2-methyl-3-propanoyl) 7-bis-L-proline is used. The title compound is obtained.

Example 137 1.1 '- / (Sulfonylthioj-bisacetvlJ-bis-L-hydroxvproline

Example 127 is repeated with the change that instead of 1,1 '- / dithiobis- (3-propanoylj ^ -bis-L-proline the 1,1 '- (Dithiobisacetyl) -bis-L-hydroxyproline is used. The title compound is obtained.

Example 138

1.1 '- / TSulfonylthio) bis (3-propanovl) 7-bis-1-piperidine-2-carboxylic acid

Example 127 is repeated with the change that instead of 1,1 '- / pithiobis- (3-propanoyl ^ 7-bis-L-proline the L -I

709833/1005

1,1 '- / (Dithiobis- (3-propanoyl) _7-bis-L-piperidine-2-carboxylic acid is used. The title compound is obtained.

Example 139

1,1 '- / (sulfonylthio) -bis- (5-propanovl) y-bis-5-hvdroxv-L-piperidine-2-carboxylic acid

Example 127 is repeated with the change that instead of 1,1 »- / dithiobis- (3-propanoyl-7-bis-L-proline the ¹ » ¹ '-zpithiobis- (3-propanoyl) / - bis-5-hydroxy- : L-piperidine-2-carboxylic acid is used The title compound is obtained.

Example 140

1,1 '- / (sulfonyl thio) -bis- (2-riethyl-3-propanovl 17-bis-L-p.iperidine-2-carboxylic acid

Example 127 is repeated with the change that instead of 1,1 '- / dithiobis- (3-propanoyl) _7 ~ bis-L-proline the 1,1 '-j / Oithiobis- (2-methyl-3-propanoyl) 7-bis-L ~ piperidine-2-carboxylic acid is used. The title compound is obtained.

Example 141 1.1 ^l - / "(sulfonylth.lo) -bis- (2-benzyl-4-butanovl) 7 - bis-L - proline

Example 127 is repeated except that instead of of 1,1 '- / dithiobis- (3-propanoyl) 7-bis-L-proline das 1,1 '- / pithiobis- (2-benzyl-4-butanoyl) 7-bis-L-proline are used will. The titer connection is obtained.

Example 142 3-Acetylthio-2-phenylpropionic acid

Example 25 is repeated with the change that 2-phenylacrylic acid is used instead of methacrylic acid. It the title compound is obtained.

27G3828

1- (3-Acetylthio-2-phenylpropanoyl) -L-proline tert-butyl ester

Example 28 is repeated with the change that instead of of 3-acetylthio-2-methylpropionic acid, 3-acetylthio-2-phenylpropionic acid is used. The title compound is obtained.

Example 143 1- (3-Mercapto-2-phenylpropanovl) -L-proline

Game 29 is repeated with the change; that instead of 1- (3-acetylthio-2-methylpropanoyl) -L-proline tert-butyl ester the 1- (3-acetylthio-2-phenylpropanoyl) -L-proline tert-butyl ester is used. The product obtained is then subjected to ammonolysis according to Example 34.

Example 144 1 - / B- (Acetyl thio) -DL-propanoyl _ / - piperidine-2-carboxylic acid

6.5 g of piperidine-2-carboxylic acid are suspended in 200 ml of dimethylacetamide and 8.3 g of 3-acetylthiopropanoyl chloride are added dropwise at a temperature of 23 ° C. A clear solution is formed and the temperature rises to 28 ° C. 10.1 g of N-methylmorpholine are then added to the solution obtained. A precipitate forms immediately and the temperature rises to 34 ° C. The mixture is then heated on the steam bath for 1 hour, again forming a clear solution. The solution is then cooled and the deposited precipitate is filtered off. Yield: 5.1 g of the title compound, melting at 190 to 200 ⁰ C. Subsequently, the filtrate is evaporated and the viscous residue with Diisopro treated pyläther. A further 7.8 g of product with a melting point of 98 to 101 ^° C. are obtained. This product is recrystallized from a mixture of acetone and hexane. A constantly melting solid with a melting point of 102 to 10 ° C. and an R _f value of 0.72 (silica gel, benzene, acetic acid, 7: 2) is obtained.

709833/1005

Example 145 DL-1-f 1-mercaptopropanoyl) piperidine-2-carboxylic acid

12 ral of concentrated ammonia are stirred for about 15 minutes at a temperature of 1O ⁰ C under nitrogen as protective gas and then at a temperature of 5 to 10 ^0. C with 6.6 g of 1- / 3- (Acetylthio) -DL-piperidin-propanoyl7 -2-carboxylic acid added. A clear solution is obtained after 2 to 3 minutes. The ice bath is then removed and the solution is stirred at room temperature for 45 minutes under nitrogen as a protective gas. The mixture obtained is then made strongly acidic with 20 percent hydrochloric acid while cooling. The separated oil is extracted three times with 150 ml of ethyl acetate each time. The ethyl acetate extracts are then combined, dried over magnesium sulfate and evaporated. Yield 6.0 g of the title compound of R ^ -V / ert 0.77 (silica gel, benzene, acetic acid, 7: D.

Example 146

1- (3-Mercat) toprcpanoyl) -L-piperidine-2-carboxylic acid

Example 144 is repeated with the change that L-piperidine-2-carboxylic acid is used instead of DL-piperidine-2-carboxylic acid. The 1- / 3- (Acetylthi o) -prope.no yl / -L-piperidine-2-carboxylic acid obtained is then reacted according to Example 145. The title compound is obtained with an R ^ value of 0.80 (silica gel, benzene, acetic acid, 7: 1) and £ aj ^% - 51.5 ° (C 1.0, anhydrous ethanol).

Example 147

1- / 3- (Acetylthio) -2-methylpropanoy] 7-Dl-piperidine-2-carboxylic acid

6.5 g (0.05 mol) of piperidine-2-carboxylic acid are suspended in 200 mg of dimethylacetamide and. 9j0 g (0.05 mol) of 3-acetylthio-2-methylpropanoyl chloride were added dropwise. A clear solution is formed and the temperature rises to 29 ° C. Then 10.1 g of N-methylmorpholine are added all at once to the solution, the temperature rising ^{to 34 ° C.}

709833/1005

The resulting mixture is then heated on the steam bath for 1 hour, a clear solution again being formed. The resulting solution is kept at room temperature for about 15 hours. The precipitate which has separated out is then filtered off. Yield: 6.1 g of the Titelverbindüng mp 203-204 ⁰ C. Thereafter, the filtrate is evaporated and the viscous residue with V / ater and meant a 20 percent hydrochloric acid treated. The yellow oil obtained is extracted three times with 150 ml of ethyl acetate each time. The ethyl acetate extracts are combined, dried over magnesium sulfate and evaporated. A further 14 g of the title compound are obtained as a viscous oil.

Example 143

1- (3-Merc3.pto-2-met-hylpropanovl) -DL-piperidine-2-carbons'. ^; ure

A mixture of 30 ml V / water and 20 ml concentrated ammonia is ^{stirred at a temperature of 10 0} C for 15 minutes under nitrogen as a protective gas and then to 13.0 g (0.05 mol) of 1- / 3- (acetylthio) - 2-methylpropanoyl7 ~ DL-piperidine- ■ 2-carboxylic acid given. The solution obtained is then stirred for 10 minutes under nitrogen as a protective gas and then for 50 minutes at room temperature. The mixture is then treated with water and 20 percent hydrochloric acid. The yellow oil obtained is extracted three times with 150 ml of ethyl acetate each time. The ethyl acetate extracts are then combined, dried over magnesium sulfate and evaporated. Yield: 11.1 g of the title compound as a viscous oil with an R ^ value of 0.62 (silica gel, benzene, acetic acid, 7: 2).

Example 149 3 - / 14-Methoxyphenyl) methylthio / -2-methylpropionic acid

A solution of 8.6 g (0.1 mol) of methacrylic acid in 50 ml of 2 η sodium hydroxide solution with 15.4 g (0.1 mol) of p-methoxy-a-toluene thiol offset. The resulting mixture is then heated on the steam bath for 3 hours and then refluxed for 2 hours. After cooling, the reaction mixture is extracted with diethyl ether. The layers are separated and the aq-L -J

709833/1005

The remaining layer is acidified with concentrated hydrochloric acid and extracted with methylene chloride. The acidic extracts are then washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The semi-solid residue obtained is taken up in 50 ml of methylene chloride, diluted with 50 ml of hexane and quenched. Yield: 5.5 g of the title compound as a colorless crystalline solid with a melting point of 74 to 82 ^° C.

Example 150

1- / 3- (4-methoxyphenyl) methylthio / -2-methylpropanoyl-L-proline tert-butyl ester

3.6 g (0.015 mol) 3- / 14-methoxyphenyl) methyl thiq / -2-methylpropionic acid, 2.6 g (0.015 mol) L-proline tert-butyl ester and 3.1 g (0.015 mol) dicyclohexylcarbodiimide are dissolved in 50 ml of methylene chloride and ^{stirred at a temperature of 0 °} C. for 30 minutes. The cooling bath is then removed and the mixture is stirred for about 16 hours. The suspension obtained is then filtered. The filtrate is washed with 5% potassium bisulphate-saturated sodium bicarbonate and sodium chloride solution, then dried over magnesium sulphate and evaporated under reduced pressure. The clear oil obtained is chromatographed on a 250 ml silica gel column with a mixture of ethyl acetate and hexane in a volume ratio of 20:80 as the mobile phase. The main fraction of R ^ value 0.70 (silica gel, ethyl acetate) is evaporated. Yield 5.5 g (93%) of the title _{compound as a clear oil of R f} 0.70 (silica gel, ethyl acetate) and R _f 0.60 (silica gel, diethyl ether).

709833/1005

-60-

Example 151

1 - (3-Mercapto-2-methvlT3ropanovl) -L-proline 1.2 g (0.003 mol) of the product obtained according to Example 150 »5 ml of anisole and 0.5 ml of trifluoromethanesulfonic acid are dissolved in 20 ml of trifluoroacetic acid under nitrogen as a protective gas Stored for 1 hour at room temperature. The solution is then evaporated under reduced pressure. The red residue obtained is taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated again. The residue obtained is then repeatedly treated with hexane. The remaining hexane is evaporated, leaving 0.4 g of oil. A portion of 180 mg of this oil is subjected to preparative thin-layer chromatography on 2 mm silica gel plates with a mixture of benzene and acetic acid in a volume ratio of 75:25 as a mobile phase. The band giving the strongest positive response to nitroprusside (R _f value: 0.40) is recovered. Yields 135 mg of the title compound as an oil. The thin-layer chromatogram with benzene and acetic acid in a volume ratio of 75:25 shows an R _f value of 0.40 and with a mixture of chloroform, methanol and acetic acid in a volume ratio of 50:40:10, an R _f value of 0.62.

Example 152 1- (3-Mercapto-2-D-methvlpropanovl) -L-proline 10.0 g 1- / 3- (Acetylthio) -2-D-methylpropanoyl / -L-proline are

O
at a temperature of 10 C under an argon shower

slurried in 150 ml of water. Then the obtained product is

7 09833/1005

mixed with 5 η sodium hydroxide solution and the pH of the solution was kept at 13 for 1.5 hours. The addition of sodium hydroxide solution is then stopped and the solution is acidified with concentrated sulfuric acid to a pH of 2.0. The aqueous solution obtained is then extracted three times with 150 ml of methylene chloride each time. The methylene chloride extracts are combined and evaporated. The oil obtained is taken up in ethyl acetate and filtered off. The filtrate obtained is then diluted with 30 ml of hexane. After 1/2 hour, more hexane is added and the mixture is ^{cooled to 10 °} C. for 1 hour. The crystals formed are then filtered off, washed twice with 25 ml of hexane and dried to constant weight. Yield ^, 26 g of the title compound as colorless crystals with a melting point of 100 to 102 ^° C.

Example I53

"! - (- Tosyloxy ^ -methylpropanoyl) -L-proline Example 29, method B, is repeated with the change that instead of 3-acetylthio-2-methylpropionic acid chloride, 3-tosyloxy-2-methylpropionic acid chloride is used Received title defense.

Example 154

1- (3-Acetvlthlo-2-methvlT) ropanovl) -L-prolln A solution of 1.14 g of thiolacetic acid and 3.5 ml of triethylamine in 20 ml of ethyl acetate is mixed with 3.5 g of 1- (3-tosyloxy-2- methylpropanoyl) -L-proline added. Thereafter, the mixture obtained is ^{heated to 50 °} C. for 3 hours, then cooled with

709833/1005

Diluted 100 ml of ethyl acetate and washed with dilute hydrochloric acid. The organic layer is separated, dried and evaporated to dryness under reduced pressure. Hierau: the residue obtained is dissolved in acetonitrile and washed with dicyclohexylamine offset. The crystalline precipitate is filtered off and recrystallized from isopropanol. It will be Dicyclohexamine salt of the title compound with a melting point of 187 to 188 ° C,

pc O

/ σ / ρ · - 67 (C 1.4, ethanol) obtained. The salt can be converted into the free acid with a melting point of 83 to 85 ^° C. If the solution is inoculated with a refractory compound during crystallization, an isomorphic form with a melting point of 104 to 105 ° C. is obtained.

Example 155 1- (ü-Mercaptopropanovl) -L-proline-tert-butyl ester A solution of 1.71 g (10 mmol) of proline tert-butyl ester and 1.35 g (10 mmol) of 1-hydroxy-benzotriazole hydrate in 20 ml Ν, Ν-methylformamide is treated at a temperature of 0 to 5 ⁰ C under stirring with 2.06 g (10 mmol) of Ν, Ν'-dicyclohexylcarbodiimide. The mixture obtained is then stirred for 10 minutes and then a solution of 1.06 g (10 mmol) of 3-mercaptopropionic acid in 2 ml of N, N-dimethylformamide is added. The mixture is then stirred for 1 hour at a temperature of 0 to 5 ° C and then for about 15 hours at room temperature. The precipitated N, N ^f -dicyclohexylurea is then filtered off and the filtrate is evaporated under reduced pressure. The residue obtained is taken up in ethyl acetate, thoroughly washed with saturated sodium bicarbo-L

709833/1005

washed sodium solution, dried and evaporated under reduced pressure. 2.5 g of oil are obtained, which is taken up in a mixture of ethyl acetate and hexane in a volume ratio of 1: 1 and chromatographed on a 100 g silica gel column. A mixture of ethyl acetate and hexane in a volume ratio of 1: 1 is used as the mobile phase. Yield 1. AO g (54 %) of the title compound as an oil which crystallizes out on standing. Recrystallization from a mixture of diethyl ether and hexane makes 0.9 g colorless. crystalline compound with a melting point of 55 to 60 ^° C., which is identical to the product of example 17, is obtained.

Example 156 1- (3-Mercaptopropanovl) -: L-proline

A solution of 75 mg (0.27 mmol) of 1- / 3- (ethylaminocarbonyl) -thiopropanoyl7-L-proline in 1 ml of concentrated ammonia and 1 ml of water is stored for 18 hours at room temperature under argon as a protective gas. The solution is then diluted with a small amount of water and extracted with diethyl ether. The aqueous layer is acidified with cold concentrated hydrochloric acid and extracted with ethyl acetate. The extracts are then combined, dried and evaporated under reduced pressure. The product obtained is identical to that of Example 18. The thin-layer chromatography (silica gel, benzene, acetic acid, 7: 3) gives an R _f value of 0.4.

709833/1005

Example 157

Methacrvlovl-L-proline

23.0 g (0.2 mol) of L-proline are dissolved in 100 ml of water and stirred in an ice bath while cooling. 19.6 ml (0.2 mol) of methacryloyl chloride in 25 ml of methyl isobutyl ketone are added dropwise to the solution obtained in 3 hours. At the same time, 2 η sodium hydroxide solution is added and the pH of the reaction mixture is kept at 7.0. The sodium hydroxide solution is added for a further 4 hours after the addition of the acid chloride has ended. The reaction mixture is then adjusted to pH 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The aqueous layer is then acidified to pH 2.5 and carefully extracted with ethyl acetate. The acidic extracts are washed with saline solution and dried over magnesium sulfate. The ethyl acetate solution is treated with 40 ml of dicyclohexylamine and cooled for about 15 hours. The colorless precipitate obtained is then filtered off and dried. Yield: 29 g (39%) of a colorless solid, melting at 202-210 ⁰ C. The product is recrystallized from 1.5 liters of a mixture of acetonitrile and isopropanol in a volume ratio of 3 i. 1 Ausbeutel 19.7 g of dicyclohexylamine salt of the title compound as fine colorless needles melting at 202 to 21O ⁰ C.

The salt obtained wird.in a mixture of water and Dissolved ethyl acetate and acidified with concentrated hydrochloric acid. The suspension obtained is then filtered off,

709833/1005

to remove a fine colorless precipitate, which is carefully washed with ethyl acetate. The filtrate is then saturated with sodium chloride and extracted thoroughly with ethyl acetate. The ethyl acetate extracts are combined, washed with brine, dried over magnesium sulfate and evaporated. The clear oil obtained, which solidifies, is recrystallized from a mixture of ethyl acetate and hexane. Yield: 7.5 g (83 %) of the title compound as a colorless crystalline solid with a melting point of 89 to 93 ° C. After further recrystallization, a sample melts at 95 to 98 ° C.

Example 158

1- (3-Acetylthio-2-D-methvlpropanovl) -L-proline 183 mg (0.001 mol) of methacryloyl-L-proline are dissolved in 0.5 ml of thiolacetic acid and stored at room temperature for 16 hours. The solution is then evaporated under reduced pressure. The yellow residue obtained is subjected to preparative thin-layer chromatography on a silica gel column with a mixture of methylene chloride, methanol and acetic acid in a volume ratio of 90 ι 5 I 5. 240 mg of a clear oil are isolated as the main fraction. The thin-layer chromatogram with a mixture of methylene chloride, methanol and acetic acid in a volume ratio of 90: 5 i 5 shows that 1- (3-acetylthio-2-DL-methylpropanoyl) -L-proline, corresponding to the product of Example 29, method B, with an R _f value of 0.35 and, when using benzene and acetic acid in a volume ratio of 75:25, an R _f value of 0.38.

L -J

709833/1005

■ Λ;

The oil obtained above is dissolved in 3 ml of acetonitrile, treated with dicyclohexylamine until the solution has a basic reaction and cooled. The colorless crystalline precipitate obtained is then filtered off. Yield 106 mg, mp 175-181 ° C. The dicyclohexylamine salt of the title compound with a ^{temperature of up to 188 °} C. is obtained by recrystallization from isopropanol. It.
game 29, procedure A.

to 188 ⁰ C. It is identical to the product of both

Example 159

1- / blthiobis- (2-methvl-5-propanovl) 7-bis-L-proline Example 29, method B, is repeated with the change that instead of 3-acetylthio-2-methylpropionic acid, the 3.3 ^t -dithiobis -2-methylpropionic acid is used. It is obtained - the title compound.

Example 160

1- (5-Mcrcapto-2-methvlpropanovl) -L-proline A suspension of 5.0 g of the product obtained according to Example 159 in 100 ml of 1 η sulfuric acid is mixed with 10.0 g of zinc dust and at a temperature of 18.degree Stirred for 4 hours under a nitrogen shower. The mixture is then filtered. The zinc is washed with 20 ml of water, the filtrate is combined with the washing liquid and extracted three times with 75 ml of methylene chloride. The methylene chloride extracts are then washed with 25 ml of water and then evaporated. The oil obtained is taken up in 20 ml of ethyl acetate and filtered off. The filtrate is then with 15 ml

L -J

709833 / 100S

Hexane was added and the mixture was stirred for 15 minutes. The solution is then mixed with a further 30 ml of hexane and cooled to a temperature of 5 ° C. for 1 hour. The resulting precipitate is then filtered off, washed twice with 10 ml of hexane each time and dried. Yield: 4.17 g of the title compound as colorless crystals. The thin-layer chromatogram with benzene and acetic acid in a volume ratio of 75: .25 shows an R _f value of 0.60.

B e i s ρ i e 1 161

3-Benzylthio-2-methylpropionic acid

Example 149 is repeated with the change that instead of of p-methoxy-cc-toluene thiol the α-toluene thiol is used. The title compound is obtained.

Example 162

1- / 3- (Benzylthio) -2-methylpropanoyl7-L-proline-tert-butyl ester Example 150 is repeated with the change that instead of 3 - ^ (4-methoxyphenyl) -methyltMq / -2-methy! Propionic acid the 3-Benzylthio-2-methylpropionic acid is used. The title compound is obtained.

Example 163

1- / 3- (Benzylthio) -2-methylpropanovl / -L-proline 7.8 g of 1- / 3- (benzylthio) -2-methylpropanoyl7-L-proline tert-butyl ester are added to a mixture of 55 ml of anisole and 110 ml of trifluoroacetic acid dissolved. The solution obtained is kept at room temperature for 1 hour. Then the Lö-L "-J

709833/1005

sungsmlttel distilled off under reduced pressure, the residue taken up in diethyl ether, washed several times with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The title compound with an R _f value of 0.5 (silica gel, benzene, acetic acid, 3 * 1) or (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1) is obtained.

Example 164

1- (3-Mercapto-2-methvlpropanovl) -L-proline 0 »1 g of 1- / 5- (benzylthio) -2-methylpropanoyl7-L-proline are suspended in 10 ml of boiling liquid ammonia. Small pieces of sodium are added to the suspension while stirring until a blue color persists. The solution is then removed by adding a few ammonium sulfate crystals. The ammonia is evaporated under a stream of nitrogen. The residue obtained is then dissolved in a mixture of dilute hydrochloric acid and ethyl acetate. The organic layer is separated, dried and evaporated to dryness under reduced pressure. The title compound has an R _f value of 0.35 (silica gel, benzene, acetic acid, 3 s 1) or an R _f value of 0.5 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water 14: 1: 2: 1) which is identical to the product of Example 34.

Example 165

3-Trlphenylmethylthlo-2-methylpropionic acid A solution of 1.2 g of 3-mercapto-2-methyl propionic acid and L.

709833/10 05

Trityl chloride ^ βϋ

2.9 g of V in 50 ml of methylene chloride is stored for 2 hours at room temperature, then heated on the steam bath for 20 minutes and then evaporated to dryness under reduced pressure. The residue obtained is dissolved in saturated sodium bicarbonate solution and washed with ethyl acetate. The aqueous phase is then acidified to pH and extracted with ethyl acetate. The organic layer is separated, dried and evaporated to dryness. The title compound with an R _f value of 0.8 (silica gel, benzene, acetic acid 3: 1) is obtained.

Example 166

1- / ^r 3- (Triphenylmethylthio) -2-methylpropanovl7-L-proline tert-butyl ester

Example 150 is repeated with the change that instead of 3 - / ^ 4-methoxyphenyl) -methylthJoA2-methy! Propionic acid the 3-triphenylraethylthio-2-methylpropionic acid is used. The title compound is obtained.

Example 167 1- / 3- (Trlphenvlmethvlthio) -2-methylpropanovl / -L-proline

1.8 g of 3-triphenylmethylthio-2-methylpropionic acid and 0.8 g of Ν, Ν'-carbonyldiimidazole are dissolved in 10 ml of tetrahydrofuran at room temperature while stirring. After 20 minutes, the solution obtained is added to a mixture of 0.6 g of L-proline and 1.0 g of N-methylmorpholine in 20 ml of dimethylacetamide. The resulting mixture is then stirred at room temperature for about 15 hours, then evaporated to dryness and the residue is taken up in a mixture of ethyl acetate and 10 percent potassium bisulfate solution. The organic layer is separated, dried and evaporated to dryness under reduced pressure. The title compound is obtained with an R _f value of 0.4 (silica gel, benzene, acetic acid 3: 1) or an R _f value of 1.0 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water 14: 1: 2: 1) .

709833/1005

Example 168 1- (3-Mercapto-2-methvlpropanovl) -L-proline

5 g of 1- / 3- (triphenylmethylthio) -2-methylpropanoyl7-L-proline tert-butyl ester are dissolved in a mixture of 55 ml of anisole and 110 ml of trifluoroacetic acid and 1 hour at room temperature kept. The solvents are then distilled off under reduced pressure. The residue obtained is on a silica gel column in equilibrium with a mixture of benzene and acetic acid in a volume ratio of 75 I 27 with the chromatographed the same solvent as the eluent. the Fractions with the compound with the R ^ value 0.40 (silica gel with the same solvent) are collected and used Evaporated dry. It becomes the title compound of the R ^ value 0.62 (silica gel, chloroform / methanol: acetic acid, water, 50: 40: 10) obtained with the product of Example 34 is identical.

Example 169 3 * (Tetrahydropvran-2-vlthio) -2-methylpropionic acid

A solution of 2.4 g of 3-mercapto-2-methy! Propionic acid and 1.9 g freshly distilled 2,3-dihydro-4H-pyran in 60 ml 2.8 g of boron trifluoride etherate are added to benzene. The received After 2 hours, the mixture is mixed with 4 g of potassium carbonate, stirred and filtered off. Then the filtrate evaporated to dryness. The title compound is obtained.

Example 170 1- / 3- (Tetrahydropvran-2-vlthio) -2-methylpropanov17-L-proline

Example 167 is repeated with the change that 3- (tetrahydropyran-2-ylthio) -2-methyl propionic acid is used instead of 3-triphenylmethylthio-2-methyl propionic acid. The title compound has an R _f value of 0.8 (silica gel, benzene, acetic acid, 3: 1) or an R _f value of 0.75 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1 ) obtain.

709833/1005

Example 171 1- (3. Mercapto-2-methvlpropanoyl) -L-proline

A solution of 1 g of 1- / 3- (tetrahydropyran-2-ylthio) -2-methylpropanoyl / -L-proline in a mixture of 25 ml of methanol and 25 ml of concentrated hydrochloric acid is stored at room temperature for 30 minutes. The solvents are then distilled off under reduced pressure. The title compound has an R _f value of 0.35 (silica gel, benzene, acetic acid, 3 i1) or an R ^ value of 0.5 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14; 1: 2: 1) which is identical to the product of Example 34.

Example 172

3-acetamidomethylthio-2-methylpropionic acid

2.4 g of 3-mercapto-2-methylpropionic acid and 1.8 g of N-hydroxymethylacetamide are dissolved in trifluoroacetic acid and stored for 1 hour at room temperature. Then the trifluoroacetic acid distilled off under reduced pressure. The residue obtained is over under reduced pressure Potassium hydroxide; the title compound is obtained.

Example 173 1/3 (acetamidomethylthio) -2-methylpropanov17-L-proline

Example 170 is repeated with the change that 3-acetamidoraethylthio-2-methylpropionic acid is used instead of 3- (tetrahydropyran-2-ylthio) -2-methylpropionic acid. The title compound has an R _f value of 0.2 (silica gel, benzene, acetic acid, 3 ί 1) or an R _f value of 0.3 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1 j 2: 1 ) obtain.

7 0 9 8 3 3/1005

Example 174 1- (3-Mercapto-2-methylpropanovl) -L-proline

1.4 g of 1- / 3- (Acetainidomethylthio) -2-methylpropanoyl7-L-proline and 1.93 g of mercury acetate are dissolved in a mixture of 25 ml of acetic acid and 25 ml of water and stirred on the steam bath for 1 hour. The hydrogen sulfide is then passed into the solution until the mercury sulfide has completely precipitated. The mixture is then filtered off, the precipitate is washed with ethanol and the filtrate is evaporated to dryness under reduced pressure. The title compound has an R _f value of 0.35 (silica gel, benzene, acetic acid, 3 ί 1) or an R _f value of 0.5 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1 ) which is identical to the product of Example 34.

Example 175

1- (3-Mercapto-2-methylpropanovl) -L-proline-tert-butyl ester

A solution of 1.2 g (10 mmol) of S-mercapto ^ -methylpropanoic acid and 1.7 g (10 mmol) of L-proline tert-butyl ester in 25 ml of methylene chloride is cooled to a temperature of 5 ⁰ C and treated portionwise with a solution of 2.26 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride. The mixture obtained is then stored for 2 hours at room temperature and then 5 drops of acetic acid are added. The mixture is then filtered off and the filtrate is evaporated to dryness. The oily residue obtained is taken up in 20 ml of a mixture of petroleum ether and ethyl acetate in a volume ratio of 3 i 1 and chromatographed in a 150 ml silica gel column filled with petroleum ether. The fraction eluted with a mixture of petroleum ether and ethyl acetate in a volume ratio of 1: 1 contains Taer Ti te oil compound. It is dried over phosphorus pentoxide under reduced pressure for 12 hours. . R _f value 0.6 (silica gel,

Benzene, acetic acid, 3: 1) or from the R _f 0.8 (silica gel, Methyläthy ketone, acetic acid, pyridine, water, 14: 1: 2: 1).

709833/1005

Example 176
1- (3-mercapto-2-methylpropanovl) -L-proline

Example 18, method C, is repeated with the change that, instead of 1- (3-mercaptopropanoyl-L-proline tert-butyl ester, 1- (3-mercapto-2-methylpropanoyl) -L-proline tert- butyl ester is used »The title compound of R _f value 0.35 (silica gel, benzene, acetic acid, 3: 1) or R _f value 0.5 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1 : 2; 1) obtained which is identical to the product of Example 34 ..

The products of the above examples are obtained as racemates if, instead of the L-form, the starting compound the amino acid used is the DL form.

By using the D-form of the starting compound used Amino acid instead of the L-form can likewise be given the D-form of the products of the preceding examples will.

709833/1005

Claims (1)

Claims 1J Proline derivatives and related compounds of the general nen formula I. ^R 2 ~ ^S - ⁽ $ ^H > n-? ^H - ^C0 - N ςκ-COR in which R is a hydroxyl or amino group or a lower alkoxy radical, R ₁ and R ^ are hydrogen atoms, lower alkyl radicals, phenyl groups or phenyl-substituted lower alkyl radicals, Rp is a hydrogen atom, a lower alkyl radical, a PheHyF ^r or a halogen atom, a lower alkyl -, a lower alkoxy, a phenyl-substituted lower alkyl, a diphenyl-substituted lower alkyl, a triphenyl-substituted lower alkyl, a lower alkylthiomethyl, a phenyl-substituted lower alkylthiomethyl, a lower alkanoylamidomethyl radical or by one of the radicals OM M R ₅ -C-, R ₅ -MC-, R ₅ -NH-C-, ^R 6-S- or R ₇ substituted phenyl group means R, a hydrogen atom, a hydroxyl group or a lower alkyl group, R ₅ a lower alkyl group, a phenyl group or a phenyl-substituted lower alkyl group and Rg a lower alkyl group, a phenyl group, a halogen atom, a lower alkyl or lower alkoxy group substituted phenyl group, a hydroxy-substituted lower alkyl or an amino- (carboxy) -substituted lower alkyl radical, Ry represents the radical ³ : (HC) —CH ₂ R ₁ R-OC-HC N CO CH (CH) _n -S (O) _n ! OR.G.NAL, NSPECTED ^{7 09833 / S} represents, M represents an oxygen or sulfur atom, m has a value from 1 to 3 and η and ρ have a value from 0 to 2, as well as their basic salts. 2. Compounds according to claim 1 of the general formula I, in which R is a hydroxyl group or a lower alkoxy radical, R-j is a hydrogen atom or a lower alkyl radical, Rp is Hydrogen atom or one of the radicals Rc-CO-, R5-S- or Ry means, R, and R ^ each represent a hydrogen atom, Rc a lower alkyl radical or a phenyl group, Rg a lower one Alkyl radical and Ry a radical of the formula η ι ¹ ι ⁴ ; _R _ _oc 1 N-CO-CH- (CH) _n -S- represents, in which R, Rj and R ^ have the meaning given above, ra has the value 2 and η has the value 0, 1 or 2. 3 Compounds according to Claim 1 of the general formula I, in which R, and R ^ are hydrogen atoms. 4. Compounds according to claim 1 of the general formula I, in which m is 2 and R 1 is a hydrogen atom. 5 Compounds of the general formula II I Γ J ™ Rj - S - (CH ₂ ) jp - CH - CO - N L - COR in which R is a hydroxyl group or a lower alkoxy radical, RJ is a hydrogen atom or a lower alkyl radical and R _{2 is} a hydrogen atom or a lower alkanoyl radical, and η is 0, 1 or 2 and its salts. 709833/1005 6. connections according to claim 5 of the general formula II, in which R is a hydroxyl group. 7 Compounds according to Claim 5 of the general formula II, in which η has the value 1. 8. Compounds according to claim 5 of the general formula II, in which R _{2 is} a hydrogen atom or a lower alkanoyl radical. 9. Compounds according to claim 5 of the general formula II, in which R _{2 is} a hydrogen atom. 10. Compounds according to claim 5 of the general formula II, in which R _{2 is} an acetyl group. 11. Compounds according to claim 5 of the general formula II, in which R ₁ denotes a hydrogen atom or a lower alkyl radical. 12. Compounds according to claim 5 of the general formula II, in which R _{1 is} a hydrogen atom or a methyl group. 13. Compounds according to claim 5 of the general formula II, in which R is a hydroxyl group and R _{1 is} a hydrogen atom or a methyl group. 14. Compounds according to claim 5 of the general formula II in which R represents a hydroxyl _r R ₁ is a hydrogen atom or a methyl group, R ₂ represents a hydrogen atom or an acetyl group and η is 0, 1 or. 2 15. Compounds according to claim 5 of the general formula II, in which R is a hydroxyl group and R ₁ and R _{2 are} each a serstoffatoa and η has the value 0. 709833/1005 16. Compounds according to claim 5 of the general formula II, in which R is a hydroxyl group, R _{1 is} a hydrogen atom and R _{2 is} an acetyl group and η is 1. 17. Compounds according to claim 5 of the general formula II, in which R is a hydroxyl group, R _{1 is} a methyl group and Ro is an acetyl group and η is 1. 18. Compounds according to claim 5 of the general formula II, in which R is a hydroxyl group and R ₁ and R _{2 are} each a hydrogen atom and η is 1. 19 «Compounds according to claim 5 of the general formula II, in which R is a hydroxyl group, R _{1 is} a methyl group and R _{2 is} a hydrogen atom and η is 1. 20. Compounds according to claim 5 of the general formula II, in which R is a hydroxyl group, R _{1 is} a hydrogen atom and R _{2 is} a benzoyl group and η is 1. 211 compounds according to claim 5 of the general formula II in the L shape. 22> Compounds according to claim 1 of the general formula I in which R is a hydroxyl group, R _{1 is} a hydrogen atom and R _{2 is} a lower alkylthio radical and η is 1. 23 ' Compounds according to claim 1 of the general formula I, in which R _{2 is} a radical of the formula _R -0C 1 N-OC-CH- (CH ₂ ) _n -S- R is in each case a hydroxyl group and R _{1 is in} each case a hydrogen or a lower alkyl radical and η has the value O, 1 or 2. 709833/1005 24. Compounds according to claim 23, of the general formula I, in which R is in each case a hydroxyl group and R _{1 is} a hydrogen atom and η is 1. 25 x 1- (3-mercapto-2-D-methylpropanoyl) -L-proline. 26. 1,1 '- / dithiobis (2-D-methyl-3-propanoyl 17-bis-L-proline. 27 · Connections according to claim 17, 18 or 19, characterized characterized in that the proline ring is in the L-form. 28. Process for the preparation of the compounds of the general formula I, characterized in that a compound of the general formula III I ³ (in) H ₂ C (CH) _m j I I HN CH COR with a carboxylic acid of the general formula IV R "R ₁ : I ⁴ I ¹ ■ (IV) R ₂ S (CH) ₅ CH COOH or their chemical equivalent, and the compound obtained is optionally reacted with a base to form a salt. 29. Medicines with angiotensin converting enzyme blocking effect, characterized by a content of one A compound according to Claims 1 to 27. 709833/1008