DD145749A5 - METHOD FOR PRODUCING MERCAPTOACYL DERIVATIVES OF SUBSTITUTED PROLINES - Google Patents

Abstract

The invention relates to a process for the preparation of mercaptoacyl derivatives of substituted prolols of the general formula I and their salts with bases, where the radicals have the meaning given in the invention claim. The compounds prepared according to the invention are valuable drugs for the treatment of hypertension. - Formula I -

Description

Field of application of the invention:

The application of the present invention is in the field of drugs for the treatment of hypertension,

Characteristics of the known technical solutions:

Publications that the. present invention as the prior art are currently unknown.

Target de r Erf indung;

The aim of the invention is to provide new drugs for the treatment of hypertension.

Explanation of the essence of the invention; , ,

The invention has the object of providing new drugs ^ ⁰ for the treatment of hypertension, which prevent the conversion of the decapeptide angiotensin I to angiotensin II. And are therefore useful for the reduction or elimination of hypertension.

The invention accordingly relates to a process for the preparation of mercaptoacyl derivatives of substituted prolols of the general formula I.

X-R

R ₃ R ₂ W Γ I ^{2 2} I λ (D.

R ₄ - S - (CH) CHCH-CO

N c _e - COOR

and their salts with bases,

where'the rest X-R. in the 3- or 4-position of the proline ring

is bound, and. ,

X is an oxygen or sulfur atom, R is a hydrogen atom or a lower alkyl radical, R is a lower alkyl, lower alkenyl or lower alkynyl radical, an optionally substituted phenyl group or an optionally substituted phenyl-lower-alkylene radical, R "and R ₃ independently of one another are hydrogen atoms, lower alkyl radicals or trifluoromethyl groups, 0 R _{4 is} a hydrogen atom, the radical RC-

L _J

or the rest

ί ² - N X-R ³ - CH - I -S- (CH) - H CO

COOR

and R is a lower AlkyIrest, a phenyl group or a phenyl-lower-alkylene radical and η is 0, 1 or 2, characterized in that a proline derivative of the general formula II

XR

HN C-COOR

in the X, R and R _{1 have} the meaning given above, with a carboxylic acid derivative or its chemical equivalent of the general formula III

^R -i ^R 2

ι ι

R '-s (cH) -CH-COOH (III)

"4 · η

in the R _? , R ^ and η have the abovementioned meaning and R 'is a hydrogen atom or the radical R ₁ ^ -CO- represents ₇ to give a compound of general formula I in which R is a hydrogen atom or a radical R ₅ -CO- optionally, the resulting compound in which R _{4 is} the radical R, - CO- hydrolyzed to a compound of general formula I in which R. is a hydrogen atom, for the preparation of the compounds of general formula I, in the R ₄ the rest

XR,

-S- (CII) CH - CO - Ν - C - COOH

η j

represents, the resulting compounds of general formula I in which R. is a hydrogen atom, oxidized with iodine, and. if appropriate, the resulting compounds of the general formula I are converted into a salt with a basein.

  The invention thus relates to the preparation of ether and thioether mercaptoacyl-prolines of the general formula I. Furthermore, the invention relates to the use of these compounds for the treatment of high blood pressure.

Dili designation, "lower alkyl" in the definition of the radicals R, R ₁ , R ₀ and R ~ means branched or unbranched hydrocarbon radicals with at most. 7 carbon

atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and isopentyl. Preferred are lower alkyl radicals having at most 4 carbon atoms, more preferably the methyl and

the ethyl group

   ,

The term "lower alkenyl radical" in the definition of the radical R ₁ denotes monounsaturated branched or unbranched hydrocarbon radicals having 2 to 7 carbon atoms, such as the ethenyl, propenyl or isopropenyl radicals.

or butenyl group. The "lower alkynyl radicals" are branched or unbranched hydrocarbon radicals having 2 to 7 carbon atoms and a carbon-carbon triple bond, such as the propargyl group. Preferred lower alkenyl radicals have 2 to 5 carbon atoms and

*

preferably lower alkynyl radicals have 3 to 4 carbon atoms.

_: "

The term "substituted phenyl" and "substituted phenyl-lower-alkylene" in the definition of the radical R ₁ includes one or two, preferably a substituent on the phenyl ring. Suitable substituents are lower alkyl of 1 to 4 carbon atoms, especially methyl, lower Alkoxy radicals having 1 to 4 carbon atoms, in particular the methoxy group, nie-; alkylthio radicals having 1 to 4 carbon atoms, in particular the methylthio group, halogen atoms, in particular chlorine or fluorine atoms, trifluoromethyl, acetyloxy and hydroxyl groups. The hydroxyl-substituted phenyl groups and phenyl-lower-alkylene groups are obtained by hydrolysis of the corresponding acetyloxy-substituted phenyl compounds as the last step in the synthesis process.

The term "halogen atom" includes the four common attic, that is, chlorine, bromine, fluorine and iodine atoms, with chlorine, bromine and fluorine atoms being preferred.

The term "phenyl-lower-alkylene" in the definition of the radicals R ₁ and R ₅ denotes' radicals of the general formula

, - ^(c v _ra - \ O>

in which m is an integer from 1 to 4. Preferred phenyl-lower alkylene radicals are the phenylmethyl and the phenylethyl group, in particular the phenylmethyl group.

The lower alkanoyl radicals denoted by the general formula R ₅ -CO- are those having the acyl radicals of the lower (C ₉ -C ₇ ) fatty acids, for example the acetyl, propionyl, butyryl and isobutyryl groups. The lower alkanoyl radicals having at most 4 carbon atoms are preferred; particularly preferred is the acetyl group. If R _r .in the radical R 1 -CO-

- ρ ~

\. Phenyl-lower-alkylene radical, the benzoyl group is particularly preferred. "

The asterisk in the general formula I designates an asymmetric carbon atom in the proline ring. Depending on the nature of the substituents R "and R ₃ in the mercapto side chain, the compounds of general formula I may contain a further asymmetric center. They therefore occur in the form of stereoisomers or of racemic mixtures. All of these forms are the subject of the invention. The preparation described below can start from the racemate or from one of the enantiomers as starting compounds. When using the racemate as the starting compound, the stereoisomers obtained in the end product can be separated by customary chromatography or customary fractional crystallization methods. The radical XR ₁ furthermore gives a cis-trans isomerism of the compounds of the general formula I.

Preference is given to the compounds of the general formula I in which the asymmetric center is present in the proline ring in the L-configuration and, if there is another asymmetric center in the mercaptoacyl sidechain, this is present in the D-configuration.

Preference is given to the compounds of the general formula I in which R is a hydrogen atom, R is a lower alkyl radical having 1 to 3 carbon atoms or the radical

represents, in which ρ the value. 0, T or 2 has and R_ is one

Hydrogen atom, a methyl ,. Methoxy or methylthio group, a chlorine or fluorine atom, a trifluoromethyl or hydroxyl group, R _{2 represents} a hydrogen atom, a methyl or trifluoromethyl group, R

, Is hydrogen, η is 0 or 1 and R is hydrogen. Also preferred as intermediates are the. mentioned above. Compounds of general formula-T in which the radical R.

Acetyl or benzoyl group, in particular an acetyl group means.

Most preferred are the abovementioned compounds of the general formula I in which X is an oxygen atom, R _{1 is} a methyl or ethyl group, in particular a methyl group, η is 1, R 1 is a hydrogen atom or a methyl group, in particular one represents methyl group, R. a hydrogen atom and R. mean a hydrogen atom, and further, the residual XR ₁ in the 4-position

'

is bound to the proline ring, in particular those compounds in which the radical XR _{1 is present} in the cis configuration.

The preferred compounds of general formula I are

listed below.

1. The compounds of general formula I in which X represents an oxygen atom.

2. The compounds of general formula I in which X 25

a sulfur atom.

3. The compounds of the general formula I in which R. is a hydrogen atom.

4. The compounds of general formula I in which the proline ring is in the L-configuration.

5. The compounds of general formula I and their

.: Salts with bases, wherein the radical XR ₁ is attached in the 3- or 4-position of the proline ring and X is an oxygen or sulfur atom,. R is a hydrogen atom,

R _{1 is} a lower alkyl radical having 1 to 3 carbon atoms or the radical

R ^ is a hydrogen atom, a methyl or trifluoromethyl group,

R_ is a hydrogen atom,

R _{4 is} a hydrogen atom,

an acetyl or benzoyl group,

R 1 represents a hydrogen atom, a methyl, methoxy or methylthio group, a chlorine or fluorine atom, a trifluoromethyl or hydroxyl group, η is 0 or 1, and

ρ have the value 0, 1 or 2.

6. The compounds according to No. 5, in which X represents an oxygen atom.

7. The compounds according to no. 6, in which R. is a hydrogen atom and R _? e 'is a hydrogen atom or a methyl group and η is 1.

8. The compounds according to No. 7, in which R denotes a lower alkyl radical having 1 to 3 carbon atoms,

9. The compounds according to No. 8, in which the proline ring is in the L-configuration, the asymmetric carbon atom to which the radical R is attached, if R "is not a hydrogen atom, is in the D configuration and the rest -O-R ₁ is attached in the 4-position of the proline ring and is present in the cis configuration

10.The compounds of No 9, in which R, is a methyl

\ group means. ·

11. (ice) -4 ~ methoxy-1- (D-3-mercapto-2-methyl-i-oxopropyl) -L-proline.

12. (cis) -4-methoxy-1 ~ (3-mercapto-i-oxopropyl) -L-proline.

13.The compounds according to No. 8 in which the proline ring is in the L-configuration, the asymmetric carbon atom to which the radical R "is attached if R ₉ does not represent a hydrogen atom, is present in the D configuration and the ReSt OR ₁ in the 4-position of the proline ring

ff * Wp pil

<Y? rf / Va »_ Q _

  is bound and in the trans configuration.

14. The connections after no. ' -. 13; in which R is a methyl group.

15. (trans) -4-Methoxy-1- (p-3-mercapto-2-m-ethyl-1-oxopropyl}. '' L-proline.

16. (trans) -4-methoxy-i- (3-mercapto-i-oxopropyl) -L-proline.

17. The compounds according to No. 13, in which R. means an ethyl group. ,

18. (trans) -4-ethoxy-1- (D-3-mercapto-2-methyl-1-oxopropyl) -L-proline.

, The connections after xj _r . 13, in which R _{1 is} a

n-propyl group

 20. (trans) -4-propoxy-i- (p-3-mercapto-2-methyl-1-oxopropyl) L-proline

21. Pie compounds according to No. 7, in which R _{1 is} the remainder

- (CH ₂ )

and R, a hydrogen atom, a methyl, methoxy or methylthio group, a chlorine or fluorine atom represent a trifluoromethyl or hydroxyl group and ρ has the value 0, Ί or 2.

22. The compounds according to No. 21 in which the proline ring is in the L-configuration, the asymmetric carbon atom to which the radical R "is bonded if R _{2 is} not a hydrogen atom, is present in the D configuration. And the rest -O-R ₁ is attached in the 4-position of the proline ring.

23. (Ice) -4- (4-fluorophenoxy) -1- (D-3-mercapto-2-methyl-1-oxopropyl) -L-proline.

24. The compounds according to No. 5, in which X is a sulfur atom.

25. The compounds according to No. 24, in which R. a hydrogen atom and R "is a hydrogen atom or a methyl group and η is 1.

L- J

r. · · ..- π

- 10 -

.26. The. Compounds according to No. 25, in which R _{1 is} a lower alkyl radical having 1 to 3 carbon atoms. 27. The compounds according to No. 26, in which R _{1 represents} a methyl group

 28. (trans) -1- (3-mercapto-1-o.xopropyl) -3-methylthio-D, L-proline.

29. The compounds according to No. 25, in which R _{1 is} the radical

and R, a first fatoma, a methyl, methoxyb

or methylthio group, a chlorine or fluorine atom, a trifluoromethyl or hydroxyl group and ρ has the value 0, 1 or 2,

30c 1- (D-3H-ercapto-2-ethyl-1-oxopropyl) -cis-4-phenylthio-L-proline.

ο The compounds according to No. 6, in which R is an acetyl group and R "is a hydrogen atom or a methyl group and η is 1.

32. The compounds according to No. 31, in which R ₁ denotes a lower alkyl radical having 1 to 3 carbon atoms »

33. The compounds according to No. 32 in which the proline ring is in the L-configuration, the asymmetric carbon atom to which the radical R "is attached if R" is not a hydrogen atom, is present in the D configuration and the radical 0-R ₁ is attached in the 4-position of the proline ring and is in the cis configuration.

34. The compounds according to No. 33, in which R _{1 represents} a methyl group.

35. (Ice) -4-Methoxy-i- [D- (acetylthio) -2-methyl-1-oxopropyl] -L-proline. ,

36. The compounds of item 32 in which the proline ring is in the L-configuration are the asymmetric carbon

no hydrogen atom, in the D configuration

atom to which the radical R "is attached if

L -1:

15 20 ²⁵

41

42

is present and the rest -O .-. R ... is bound in 4-S.tellung of the proline ring and in the. traris configuration.

37. The 'connections to. .No. 36, in which R. represents a methyl group.

38. The compounds of No 36, in which R .. represents an ethyl group.

39. The compounds according to No. 36, in which R .. represents an η-propyl group.

40. The compounds according to No. 31, in which R _{1 is} the radical

and R, a hydrogen atom, a methyl, methoxy or

Methylthio group, a chlorine or fluorine atom, a trifluoromethyl or hydroxyl group and ρ has the value 0, 1 or 2.

The compounds according to No. 24, in which R is an acetyl group and R ~ is a hydrogen atom or a methyl group and η is 1.

The compounds according to No. 41, in which R _{1 is} a lower alkyl radical having 1 to 3 carbon atoms. 43. The compounds according to No. 41, in which R _{1 is} the radical

and R, a hydrogen atom, a methyl, methoxy or methylthio group, a chlorine or fluorine atom, a trifluoromethyl or hydroxyl group and ρ has the value 0, 1 or 2.

35

The compounds of the general formula I are obtained by reacting an ether or thioetherproline of the general formula II

Γ ^

H ₂ C 3

HN

- .12. -XR ₁

 COOK

(ID

with a carboxylic acid derivative or its chemical equivalent of the general formula III

R, R

^{13 l2} ; you)

R1 - S - (CH) - CH - COOH

4 η

in which R ' _{4 represents} a hydrogen atom or the radical R-CO-. In this reaction, the compounds of general formula IV are obtained.

R_

Γ ³

(IV)

4 _n * j

¹ , -S- (CH) -CH-CO-N ** η

The reaction may be carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide, or the carboxylic acid derivative of general formula III may be prepared by conversion into, its mixed anhydride, symmetrical anhydride, acid halide or active ester or by using the Woodward reagent K which is N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. These acylation processes are described in Houben-Weyl, Methods of Organic Chemistry, Vol. XV, Part II (1974), page 1 et seq. Preferably, the acid halide, in particular the acid chloride, of the carboxylic acid derivative of the general formula III is reacted with the proline derivative of the general formula II.

^ The esters of the general formula: IV, ie · the. Compounds in which R represents an alkyl group, can by conventional methods to the free acids in which R represents a hydrogen atom, converted to be. For example, if R

^ A tert-B.uty represents! Group, treatment, gives the free acid with trifluoroacetic acid and anisole.

Preferably, the. Compounds of general formula IV are isolated and purified by crystallization, for example by preparation of the Dicyclohexylaminsalzes, which is then converted by treatment with an aqueous solution of an acid, such as acidic potassium sulfate, in the free acid.

  The compounds of the general formula IV which contain the acyl radical R 1 -CO- can be converted by customary hydrolysis or by ammonolysis into the compounds of the general formula I in which R is a hydrogen atom

means

 20

The compounds of the general formula I in which R. is the radical.

25

-S- (CH) -CH- CO- N C ^ -COOH

can be directly obtained by oxidation of the compounds of general formula I, in the R

 represents, to be obtained with iodine ..

of the general formula I in which R _{4 is} a hydrogen atom

The esters of the general formula I in which R is a lower alkyl radical can be prepared from the free carboxylic acids of the general formula I in which R is a hydrogen

, , ,

means, obtained by conventional esterification, for example by. Esterification with a diazoalkane such as diazomethane or a 1-alkyl-3-p-tolyl triazene such as 1-n-B.utyl-3-p-tolyltri.azene.

The proline starting compounds of general formula II can be prepared by various methods. For example, a hydroxy- or mercaptoproline of the general formula V

XH H "C

HN C-COOH

I *

with an acylating agent, such as acetic anhydride, acetyl chloride, propionic anhydride, butyric anhydride or benzyl chloroformate, to protect the nitrogen atom. Thereupon, by reacting the N-protected derivative of the compound of the general formula V with a halide or a compound of the general formula R ₁ -hai, in _? T. the hai is a halogen atom, preferably an iodine atom, introduced in the presence of silver oxide, sodium hydride or sodium hydroxide, the radical R ₁ . An intermediate of the general formula VI is obtained.

XR,

H ₂ C

Protecting group -N - C _A -COOR

L -J

The alkaline hydrolysis of the intermediate of the general formula. VI with a base, such as barium hydroxide, sodium hydroxide, or potassium hydroxide initially gives the free acid (COOH). Subsequently, by hydrolysis with a mineral acid such as sulfuric acid, the starting compound of the general formula. II received. ,

A further process for the preparation of the proline starting compounds of the general formula II consists in the reaction of the tosyl-protected tosyl-containing tosyloxy-proline ester, preferably the methyl ester of the general formula VII

H "-C

OTS /

^2t '(VII)

"*

Protecting group -VC-COOalkyl

with the sodium salt of general formula VIII.

R ₁ -X-Na (VIII)

In this case, an intermediate of general formula IX is obtained.

Protecting group - _K c _A - COOalkyl. (IX)

H ·

, ·.

In the general formula VII, Ts is the group

and the protecting group on the nitrogen atom is preferably a benzyloxycarbonyl group or another commonly used

Γ _Λ Π

, ι ι 4y V ^ - .16 -

se used acyl protecting group. In this reaction, when the tosylate group is in the cis configuration, the radical XR-j is in the trans-configuration and when the tosyloxy group is in the trans-configuration, the radical XR -j received in the cis king configuration. The. Intermediate product of general formula IX 'is then treated to remove the alkyl ester residue and then reacted with hydrogen bromide. In this case, the hydrogen bromide salt of the proline starting compound of the general formula II

obtained, which can then be reacted with the carboxylic acid derivative, preferably in the form of the acid chloride, the general formula III.

The proline starting compounds of the general formula II,

in which X represents a sulfur atom and the radical xr is attached to the proline ring in the 3-position, can also be prepared by reacting a 1,2-dehydroproline ester, preferably the tert-butyl ester, of the general formula X.

• N - = x-L_COOalkyl (X)

with an acylating agent such as benzyl chloroformate or acetyl chloride. First, the 4,5-dehydro compound of the general formula XI is obtained

Protecting group-N L lkyl _COOA (XI)

which is then reacted with a mercaptan of general formula R ₁ to give a compound of general formula XII,

SR ₁

¹ ..- (XII)

Protective group " ¹ * ^ ~ COOalkyl

in which the radical -SR _{1 is} in the trans configuration. The protecting group on the nitrogen atom and the alkyl radical are subsequently removed to give the desired starting compound of general formula II.

The proline starting compounds of the general formula II, in which R _{1 represents} a phenyl group, a substituted phenyl group, a phenyl-lower-alkylene radical or a substituted phenyl-lower-alkylene radical, may also be replaced by.

Reaction of the benzyl ester of the nitrogen-protected proline derivative of the general formula V with an alcohol of the general formula R ₁ -OH in the presence of triphenylphosphine and diethyl azodicarboxylate according to the method described by Bittner et al. in Chemistry and Industry,

15 March 1975, p. 281. Removal of the protecting group from the nitrogen atom and the benzyl ester group then gives the starting compound of general formula II.

Further references for the preparation of starting compounds and intermediates can be found in the following publications: Ondetti et al., U.S. Patents 4,046,889, 4,105,776 and 4,154,935; Neuberger, J. Chem. Soc. (1945), pp. 429-4.32; Patchett et al., J. Amef. Chem. Soc. 79, (.1957) pp. 185-192; Baer et al., Can. J. Biochem. and Phys., 37, (1959), pp. 583-5.87, Sheehan et al. , J. Amer. Chem. Soc. 85 (1963), pp. 3863-3865. Magerlein, J.Med.Chem. 10. (1967), pp. 11.61-1.163. The methods described in the above publications can be used as general methods of preparation and stereo-conversion of the compounds used in the present invention.

"Jo,

The compounds of general formula I form basic salts with a variety of inorganic and organic bases. The salt-forming ions derived from the bases may be metal ions, for example, aluminum,.

Alkali metal, such as sodium or potassium or alkaline earth metal, such as calcium or magnesium ions, or amine salt ions, a number of which are known for this purpose, for example aralkylamines, such as dibenzylamine or N, N-dibenzylethylenediamine, lower alkylamines, such as methylamine, tertiary butylamine or procaine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, 1-adamantanamine, benzathiazine, or salts derived from amino acids such as arginine or lysine.

Physiologically acceptable salts, such as Natriuni-15

or potassium salts, are suitable for pharmacological use and are preferred. These and other salts, which are not necessarily physiologically acceptable, are also useful in the isolation and purification of the products, as exemplified by the example of dicyclohexylamine

and cyclohexylamine salts are shown in the embodiments. The salts are prepared by reacting the acidic form of the compounds of general formula I with one equivalent of the base yielding the desired basic ion in a medium in which the salt precipitates, or in

aqueous medium and subsequent lyophilization. The free acid can be obtained from the salt by conventional neutralization, for example with potassium bisulfate or hydrochloric acid.

The compounds of the general formula I inhibit the conversion of the decapeptide angiotensin I into angiotensin II and are therefore suitable for the reduction or reduction of hypertension. The compounds of the invention intervene in the reaction sequence renin -J angiotensinogen -> angiotensin I -> angiotensin II by

L. _J

£ I 4 & ψ k & -19-

inhibit enzyme turnover and thus reduce or eliminate the formation of the hypertensive agent angiotensin II. Therefore, by administering an agent containing at least one compound of the general formula I or its salt, hypertension can be reduced or eliminated.

A single dose, or preferably 2 to 4 separate daily dosages, formulated on the basis of about

approximately

0.1 to 100 mg / kg / day, preferably about 1 to / 50 mg / kg / day, is useful for reducing blood pressure in the S.L. Angel, T.R. Schaeffer, M.H-Waugh and B. Rubin, Proc. Soc. Animal Biol. Med. 143 (1973), p. 483. The agent is preferably administered orally; however, parenteral, such as subcutaneous, intramuscular, intravenous or intraperitoneal administration is also contemplated.

The compounds of general formula I may be formulated into tablets, capsules or elixirs for oral administration or to sterile solutions or suspensions for parenteral administration. It will be about 10

about to / 500 mg of the active ingredient with conventional carriers, excipients and additives connected to a dosage unit. The tablets or capsules may contain as excipients, for example, binders, excipients, disintegrants, lubricants / sweeteners and flavorings. Capsules may also contain a liquid carrier such as a fatty oil. Injection preparations can be formulated by conventional pharmacological methods by dissolving or suspending the active ingredient in a carrier such as water for injection, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil or cottonseed oil.

* -Ι Γ

Exemplary embodiments.

Example T- (3-acetylthio-1-oxopropy 1) -ί

a) 'N-Acetyl-trans - ^ - ydroxy- L-proline A suspension of 26.2 g (O ₇ 2 mol) of trans-4-hydroxy-L-proline in 400 ml of acetic acid is added with stirring with 26 ml acetic anhydride treated. After stirring for 2 hours at room temperature, the solid gradually dissolves.

The resulting solution is placed in a 2 liter flask and the solvent evaporated on a rotary evaporator at a bath temperature of 45 ° C. 57.5 g of syrupy residue are obtained, which is diluted with 100 ml of diethyl ether. In this case, a crystalline solid is obtained, which is cooled for about 15 hours, then filtered off, washed with cold diethyl ether and dried in a desiccator. The yield obtained of 35.7 g is pulverized and suspended in 100 ml of diethyl ether, cooled and filtered "There are 33.8 g (98%) of the title compound F, 128 to 131 ⁰ C. Recrystallization from 0.5 g of the product from 5 ml of acetonitrile gives 0.45 g of a colorless solid, mp 130 to 132 ⁰ C; [a] p ⁵ -92 ° (c, 1% in ethanol).

b) N-Acetyl-tra ns-4-methoxy-L- proline n-methyl ester A mixture of 30.0 g (0.17 mol) of N-acetyl-trans-4-hydroxy-L-proline and 130 g of silver oxide pulverized in a mortar and the resulting intimate mixture is placed in a 1 liter flask with 300 ml of acetone. The slurry is then stirred, treated portionwise with 130 ml of methyl iodide and the temperature kept below 40 ° C by cooling in a cold water bath. After stirring for 7 hours, the mixture is allowed to stand for about 15 hours. Thereafter, the solid is filtered off, washed thoroughly with acetone and the filtrate is concentrated on a rotary evaporator. There are obtained 38.3 g of a sirupösen residue, the again

^Γ % I fit ö Ü Ä

fi ι # ο V Il

- .21 -

dissolved in 350 ml of acetone and again treated with 130 g of silver oxide and 130 ml of methyl iodide. This gives 41 g of residue, which is distilled. Yield: 32.2 g of distillate of bp. 130 to 140 ° C (0.3 mm). After trituration in 30 ml of cyclohexane and cooling, 31.4 g of the title compound are obtained as a virtually colorless solid of mp 71-75 ° C. Recrystallization from 31 ml of ethyl acetate. gives 25.1 g (66%) of a colorless solid of mp 76-77 ° C; [a] p ⁵ : - 83 ° (c, 1% in ethanol).

,

c) trans-4-methoxy-L- proline ·

A solution of 27.0 g (0.085 mol) of Ba (OH) ₂ . 8H ₃ O in. 525 ml of water (about 3.3 n) is added with stirring 11.0 g (0.05 mol) of N-acetyl-trans-4-methoxy-L-proline methyl ester. The resulting solution is then stirred for 3 hours at 18 to 20 C, cooled and treated with dilute sulfuric acid (8, ξ g of concentrated sulfuric acid in 20 ml of water). The acidic suspension is allowed to stand for about 15 hours. Thereafter, the mixture is filtered through a thick layer of Celite. A "milky" filtrate is obtained, which is concentrated on a rotary evaporator at 50 ° C. using a high vacuum pump. There are obtained 121 g of a milky residue, which is treated with dilute sulfuric acid (19.0 g of concentrated sulfuric acid in 75 ml of water). The resulting mixture is refluxed for 3 hours and stirred. After cooling to 30 C, the reaction mixture is added in portions with 48 g of Ba (OH) ^. 8H ~ 0, and the pH is then adjusted with dilute sulfuric acid from 6.0 to 4.0. The mixture is allowed to stand for about 15 hours and then filtered through a thick layer of celite. The resulting "milky" filtrate is concentrated as described above to give 50 g of colorless dry residue. This is digested with 200 ml of hot chloroform and then filtered through a celite bed to remove barium sulfate. The resulting, slightly turbid filtrate is

ι-.

evaporated on a rotary evaporator. 17.7 g of a gelatinous substance are obtained, which are suspended in 100 ml of diethyl ether and then filtered. Yield: 7.5 g (94%). almost colorless solid, from mp 185 to 190 ° C (dec.). This product is suspended in 30 ml of warm acetonitrile, cooled and filtered. Yield 4.0 g (50%) of the title compound as a colorless solid of mp 209-211 ° C (dec.); [a] ^ ⁵ : -75 ° (c, 1% in ethanol). ,

d) 1- (3-Acetylthio- 1-oxo- propyl) -trans-4-methoxy-L-proline A solution of 3.5 g (0.024 mol) of trans-4-methoxy-L-proline in 50 ml of water is stirred , cooled to 5 C and treated with 3 g of sodium carbonate. The resulting mixture is then treated with a solution of 4.0 g (0.024 mole) of 3-acetylthiopropionyl chloride in 5 ml of diethyl ether over 10 minutes .wobei 3 g of sodium carbonate are added in between to adjust the pH value to about 8.0 to keep. Thereafter, the mixture is stirred for an additional hour in an ice bath. and then with 25 ml of water, followed by a solution of 5 ml of concentrated hydrochloric acid ^ in 25 ml of water (CO ^ evolution). The strongly acidic solution is then saturated with sodium chloride and extracted four times with 50 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated. Yield: 6.0 g (90%) of the title compound as a colorless syrupy material. The resulting acid is dissolved in 25 ml of ethyl acetate and treated with 4.7 g of dicyclohexylamine. This creates a solution that solidifies quickly. An additional 15 ml of ethyl acetate will be added.

and the mixture / triturated on the steam bath, cooled and filtered. Yield: 8.7 g of the dicyclohexylamine salt of the title compound, mp 170 to 17 2 ° C. After recrystallization from .60 ml of acetonitrile are 8.3 g (75%) of colorless solid, mp. 171 to 173 ⁰ C /

? 5 o

': -35 (c, 1% in ethanol).

For conversion to the title compound, the dicyclohexylamine salt (8.0 g) is suspended in 60 ml of ethyl acetate,

  which was cooled in an ice bath, 'and in portions with 60 ml

lOprozentigem

Ί potassium bisulfate treated. The clear layers are

the separated and the aqueous layers extracted twice with 60 ml of ethyl acetate. Then the organic phases are combined, dried over magnesium sulfate, filtered and evaporated. Yield: 4.6 g (80%) of the title compound

as a colorless syrupy substance. 10

Example 2

1 - (3-mercapto- 1-oxopro pyl ) -trans-4-methoxy-Lp rolin 4.6 g (0.017 mol) of the 1 ~ (3-acetylthio-1-oxopropyl) -trans-4 obtained in Example 1 methoxy-L-proline are with

a cold solution of 9 ml of concentrated ammonia in 22 ml of water. The base dissolves) in about 30 minutes and the resulting solution is allowed to stand under argon as a protective gas for 2 hours at room temperature. Thereafter, the solution is cooled, twice with 25 ml of ethyl acetate

extracted and the Äthylacetatextrakt is discarded. Thereafter, the solution is again covered with 25 ml of ethyl acetate and acidified with 17 ml of 1 ι 1 hydrochloric acid. The mixture is then shaken out, the phases are separated and the aqueous phase is washed three times with 25 ml of ethyl acetate.

extracted acetate. The organic phases are combined, dried over magnesium sulfate, filtered off and the solvent is distilled off on a rotary evaporator. Yield: 2.3 g (59%) of the title compound as a colorless

25 ο

syrupy substance [α] ~: - 60 (c, 1% in ethanol); R,.: 0.49 D f.

(MeOH on silica gel, visualized with nitroprusside)

reagent}*

Analysis for C ₉ Il ₁₅ NO ₄ S.

45 C 6 H 5 N 1 3 S About: 45 / 46 6 / 57. 5 / 87. 1 3 / 48 gef. : , 42 , 78 · , 96, , 27th

Another 1.1 g of product (total yield: 3.4 g = 87 %) are obtained by saturating the aqueous phase with sodium chloride and extracting twice with 25 ml of ethyl acetate. '

The sodium salt is obtained by treatment of the syrupy title compound with aqueous sodium bicarbonate solution and lyophilization.

Example 3

(Trans) -1- [D ~ 3- (A cet ylthio) - 2-methyl-i-oxopropyl] -4-m eth oxy-L-proline

A solution of 4.3 g (0.029 mol) of trans-4-methoxy-L-proline in 50 ml of water is stirred, cooled to 5 C and treated with 3 g of sodium carbonate. Thereafter, the resulting solution is added in the course of 10 minutes with 5.2 g (0.029 mol) of D-3- (acetylthio) -2-methylpropionyl chloride in 5 ml of diethyl ether, wherein in between 3 g of sodium carbonate are added to the pH on to hold about .8.0. So-. then the resulting mixture is stirred in an ice bath for 1.5 hours, then treated with 25 ml of water and then with a solution of 6 ml of concentrated hydrochloric acid in 25 ml of water (CO ₂ evolution) .5 The resulting strongly acidic solution is washed four times with 50 ml of ethyl acetate The organics are combined, dried over magnesium sulfate, filtered and evaporated Yield: 6.1 g (73%) of the title compound as a pale yellow syrupy residue The resulting acid is dissolved in 50 ml of ethyl acetate and treated with a solution of 4.0 g of dicyclohexylamine in 20 ml of ethyl acetate The crystallization of the product from the solution begins after about 1 minute After about 15 hours of cooling, the nearly colorless solid is filtered off and dried Yield 6.7 g, mp 175-177 ° C; [a] p ⁵ : -55 ° C (c, 1% in ethanol).

crystallization from 60 ml of acetonitrile gives 5.6 g (41%) of virtually colorless solid dicyclohexylamine salt of the title

A * b '4f _ 25 - -

binding from the F. 179 to 181 ° C; [a] ^ ⁵ : -62 ° (c, 1% in ethanol.

To convert the dicyclohexylamine salt to the free acid, this becomes (5.5 g). suspended in 50 ml of ethyl acetate, cooled in an ice bath and treated with 50 ml 10% potassium bisulfate solution. The layers are separated and

the aqueous layer is extracted twice with 50 ml of ethyl acetate, then the organic phases are combined, dried over magnesium sulphate, filtered and evaporated, giving 3.4 g (41%) of the title compound as an almost colorless syrupy material.

Example 4

(trans) - 4-methoxy-1 - (D-3-mercapto-2 -methyj _l - 1 -oxopropyI) -L-proline

3.4 g of (trans) -1- [D-3 - (acetylthio) -2-methyl-1-oxypropyl] -4-methoxy-L-proline is added with a cold solution of 8 mL of concentrated ammonia in 20 mL of water added. The base dissolves in about 10 minutes and the resulting solution is allowed to stand under argon as a protective gas for 2 hours at room temperature. Thereafter, the solution is cooled, extracted twice with 20 ml of ethyl acetate, covered with 20 ml of ethyl acetate and acidified with 15 ml of 1: 1 hydrochloric acid. Then the mixture is saturated with sodium chloride, the layers are separated and the aqueous phase extracted three times with 20 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated. Yield: 2.9 g (100%) of the title compound as an almost colorless substance; [α] _D : -80 ° (c, 1% in ethanol); Rj .: 0.53 (MeOH on silica gel visualized with nitroprusside ~ reagent)

 Analysis for C.

10 ^H 1 7 ^NO 4 S <* 1 / 4H ₂ O J 6 H N 56 1 2 S C 6 , 83. 5, 85 1 2 , 73 calc. • 47 / 69 , 84 5, , 76 gef. 47 / · 90

Γ " Λ, "

B ice ρ ie 1 5 (trans) -1 - [D-3- (Ace tylt hio) - 2-methyl-1 -oxopropyl] -A-

ethoxy-L- proline . , '.

Example 3 is repeated with the change that instead of

5 of (trans) -4-methoxy-L-proline, an equivalent amount of trans-4-ethoxy-L-proline (J. Med. Chem., 10 (1967), p. 1161) is used. It. the title compound is obtained, which is purified in the form of the dicyclohexylamine salt. After recrystallization from isopropanol, the F. is 170 to 172 ° C; [a] ^ ⁵ : -6.4 ° (c, 1% in ethanol).

The salt (7.75 g) is converted to the free acid by treatment with potassium bisulfate solution according to Example 4. Yield: 4.85 g of the title compound as an almost colorless syrupy substance.

<> At-game 6

(trans) -4-ethoxy-1- (D-3-mercapto-2-methyl-1-oxopro pyl) -L-proline

4.85 g'der of the compound obtained in Example 5 are added to a cold solution of 9 ml of concentrated ammonia in 22 ml of water under argon as inert gas. The resulting mixture is worked up according to Example 4. Yield 4.2 g (100%) of the title compound as a near-colorless syrupy material; [α] _Q : -80 ° (c, 1% in ethanol); R ^: 0.64 (MeOH on silica gel visualized with nitroprusside reagent)

Analysis for C _n H ₁₉ NO ₄ S: CHNS

Calculated: 50.55 7.33 5.36 12.27 Found: 50.34 7.34 5.39 12.11

Example 7.

(Ice) -1- [D-3- (Acetyltio ) -2-methyl'-1- oxopyryl ] -4-methoxy-L-proline ^A ^ N-carbobenzyloxy-cis-4-hydroxy-L-proline 10 g (0.038 mol) of N-carbobenzyloxy-4-keto-L-proline are dissolved in

L _J

₄

Methods described solved \ 300 ml of methanol, and 5.8 g (0.15 mol) of sodium borohydride in 20 ml of water after 79 in JACS (1957), pp reduced. There are obtained 8.7 g of a foamy product, which is dissolved in 30 ml of ethanol, treated with 3.5 g of cyclohexylamine in a little ethanol and diluted to 500 ml with diethyl ether. After addition of seed crystals and rubbing, the crystalline cyclohexylamine salt precipitates rapidly. Yield 10.8 g of the salt, mp 163-165 ° C. The Cyclohexylaminsalz is then treated with 30 ml of 2 η hydrochloric acid and then extracted four times with 50 ml of ethyl acetate. Yield: 8 g of the title compound as a glassy solid. ,

k) N-Carbobenzyloxy-cis -methoxy-L-prolinate methyl ester 13.9 g (0.052 mol) of N-carbobenzyloxy-cis-4-hydroxy-L-proline are prepared according to. Example 1 (b) was treated with 40 g of silver oxide and twice 40 ml of methyl iodide in acetone (initially 100 ml, then 120 ml). Yield 17.5 g (100%) of the title compound as a yellow oil.

°) N-Carbobenzyloxy-cis-α-methoxy-L-proline 17.5 g (about 0.052 mol) of the N-carbobenzyloxy-cis-4-methoxy-L-proline methyl ester obtained above are dissolved in 135 ml of methanol, dropwise at a temperature of -1 to 4 ° C with 32 ml (0.064 mol) of 2 η sodium hydroxide solution, then held for 1 hour at 0 ⁰ C and then for 15 hours at room temperature. Then about half of the solvent is distilled off on a rotary evaporator. Thereafter, the solution is diluted with 300 ml of water, washed with diethyl ether (the washing liquid is discarded), acidified with cooling with 12.5 ml of 1: 1 hydrochloric acid to pH 2 and finally extracted four times with 150 ml of ethyl acetate. The extracts are combined, dried over magnesium sulfate, filtered and evaporated. Yield 15 g of an orange-yellow syrupy substance dissolved in 60 ml of ethanol, with 6 g of cyclohexylamine in 10 ml of ethanol.

^ nol and diluted with diethyl ether to 900 ml. Is diluted. After addition of seed crystals and rubbing, the cyclohexylamine salt of the title compound is precipitated ... Yield after about 15 hours of cooling: 10.2 g from mp. 148 to 150 ° C (sintering at 144 ° C; 'Ea] ^ ⁶ - -35 ° (c, 1% in ethanol).

After recrystallization from 40 ml of acetonitrile, 8.8 g of the salt as a nearly '. Colorless solid from mp 150: to 152 ° C (S: in ethanol).

to 152 ° C (sintering at 145 ° C) obtained; [a] Z. : -34 ° (c, 1

The cyclohexylamine salt is treated with hydrochloric acid, yield: 6.9 g (48%) of the title compound as a pale yellow ν is

'2 (D.

koser syrupy fabric; [α] _n : 32 ° (c, 1% in ethanol).

O -4-Methoxy-L-proline A mixture of 6.8 g of N-carbobenzyloxy-cis-4-methoxy-L-propanol, 210 ml of a mixture of methanol and water in water

5 percent ratio 2: 1 and 2.3 g / palladium on carbon is 4 hours at a hydrogen pressure of 3 atmospheres

hydrogenated. The mixture is then filtered to remove the catalyst and the filtrate is evaporated. Yield: 3.15 g of a pale gray solid of mp 218 to 220 C (dec.). A sample is recrystallized from a mixture of methanol and diethyl ether. The title compound is obtained as a colorless solid of mp 224-226 ° C (dec.); [a] ^ ⁵ - 42 ° (c, 1% in methanol).

analysis for C 6 ^H 11 ^NO 3 ^: 49 C 7 H 9 N calc .: 49 , 64 7 , 64 9 65 Found .: , 63 , 71 , 54 ..

e) (ice) -1- [D-3- (acetylthio) ] - methyl-i- oxopropyl] -4-

methoxy-L-proline According to Example 3, 3 g (0.021 mol) of cis-4-methoxy-L-

proline and 4.2 g (0.023 mol). D-3-acetylthio-2-methyl-35

Propionyl chloride in 5 ml of diethyl ether in 60 ml of water in the presence of sodium bicarbonate reacted. It will be about

r ^ _Α " π

<(Weight / VolumeJ

20 ml 25% sodium carbonate soluble / required to initially adjust the pH to 8.5 and then maintain at 7.5 to 8.4 during the acylation. There are obtained 6.4 g of viscous crude product which is dissolved in 50 ml of ethyl acetate and treated with 3.9 g of dicyclohexylamine in 20 ml of ethyl acetate. The product crystallizes from the solution and is filtered off and dried. Yield: 6.6 g of Dicyclohexylaminsaaz.es the title compound of

F. 172 to 174 ° C (sintering at 170 ° C); [a] ^ ⁶ : -60 ° (c, 1 in ethanol). 6.5 g of the product are recrystallized from 35 ml of acetonitrile. Yield: 6 g of the salt as a colorless solid, mp. 17.3 to 175 ° C (sintering at 170 ° C) [a] p ⁶ : -60 ° (c, 1% in ethanol).

Analysis for C ₁₀ H NO ₁ -Sj 15 " ^{z | y D}

2 ^H 23 ^N: 61 C 9 H 5 N 6 S calc .: 61 24 8th 00 5 95 6 , 81 gef. : 16 , 81 95 , 67

According to Example 3, the dicyclohexylamine salt (5.9 g)

by suspending in 60 ml of ethyl acetate, cooling in ice-20

bath and treatment with 60 ml of a 1Oprozentigen potassium bisulfate converted into the free acid. The layers are separated and the aqueous phase extracted four times with 50 ml of ethyl acetate. Then the organic phases are combined, dried over magnesium sulfate, filtered and evaporated. Yield: 3.5 g (60%) of the title compound as a colorless solid, mp. 90 to 92 ° C (after digestion with diethyl ether); [α] _β : -139 (c, 1% in ethanol); R _£: 0.63 (methanol on silica gel). ·.

Analysis for C ₁₀ H _1n NO ^ S: CHN · 12 19 5

calculated: 49.81 6.62 4.84 found: 49.85 6.66 4.97

Example 8 (ei s) -4-Methoxy-1- (D-3-mercapto-2- methyl-1-oxopropyl) -L-

proline

According to Example 4, 2.9 g (0.01 mol) of (ice) -1- [D-3- (acetic acid)

tylthio) -2-methyl-1-oxo-propyl3J-4-m-ethoxy-L-proline in

15 ml of water containing 6.5 ml of concentrated ammonia, hydrolyzed .. Yield 2.3 g (93%) of the. Title Compound as a strong, viscous liquid which grows on standing.

becomes like; [α] ρ ^6: -8.8 ° (c, _1% in ethanol).

B e i s ρ i e 1 8 a

(Ice) -4-Methoxy-1- (D-3-mercapto-2-methyl -1 -oxopropyl) -L-proline-1-adamantanamine salt ".

A solution of 0.55 g (0.0022 mol) of cis-4-methoxy-i- (D-3-mercapto-2-methyl-1-oxopropyl) -L-proline in 15 ml of ethyl acetate was added under argon Inert gas is treated with a warm solution of 0.34 g (0.0022 mol) of 1-adamantanamine in 10 ml of ethyl acetate. The precipitated salt is allowed to stand for 3 hours in the cold. Thereafter, the colorless solid is filtered off under argon as a protective gas (the solvent is persisted), washed with a little cold ethyl acetate and dried under reduced pressure for 20 hours. Yield: 0.7 g (7%) of the title vsr

Binding from F "215 to 217 ° C (sintering at 210 ^Ο α _; decomp .: 22O ° C); [a] p ⁶ : -60 ° (c, 1% in methanol).

Example 9

( ice) - 4-methoxy-1- ( 3-mercapto-2-methyl -1-oxopropyl) -L-

prolix . ,

a) (Ice) - ^ 4-Methoxy- 1 - [3 - (benzoyltiHo ) -2-methyl-1-oxo- propyl] -Lp roline .

According to Example 3, 3-benzoylthio-2-methylpropionic acid chloride, which is obtained by treatment of 3-benzoylthio-2-methyl

Propionic acid was prepared with thionyl chloride, with

cis-4-methoxy-L-proline reacted. It will get the title compound.

b) (ice) -4-methoxy-1- (3-mercapto-2-methyl-T-oxopropyl) -L-

proline

By hydrolysis of (ice) - 2-methoxy-1 - [3- (benzoylthio) -

- .31 -

2-m.ethyl-i-oxopropyl] -2-proline with an aqueous ammonia solution according to. Example 4, the title compound is obtained. ,

In. s ρ i. e 1 10 (trans) -1- [D-3- (acetylthio ) -2- methy1-1-oxopropyl] -4 - propoxy-L-proline

a) N-Acetyl-trans -propoxy- L-proline propyl ester According to Example 1 (b), 30 g of N-acetyl-trans-4-hydroxy-L-proline from Example 1 (a) are mixed with 110 g of silver oxide and 110 ml of propyl iodide in 300 ml of acetone. Yield: 19.6 g (41%) of the title compound, as a pale yellow-orange liquid of boiling point 155 ° to 165 ° C. (0.2 now).

b) N-acetyl -trans-4-propoxy-L-proline 19.4 g (0.075 mol) of N-acetyl-trans-4-propoxy-L-proline propyl ester are treated with a solution of 6 g (0.15 mol) Sodium hydroxide in 150 ml of water. A pale orange solution is obtained which is allowed to stand at room temperature for about 15 hours. The solution is then extracted with 60 ml of ethyl acetate (the washing liquid is discarded), then acidified with 1: 1 hydrochloric acid, saturated with sodium chloride and extracted three times with 50 ml of chloroform. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated. Yield: 12.6 g of brown oil, which is dissolved in 80 ml of ethyl acetate and treated with a solution of 10.7 g of dicyclohexylamine in 20 ml of ethyl acetate. The . Salt crystallizes at room temperature. It is allowed to stand for about 15 hours with cooling, then filtered off and washed with cold ethyl acetate. Yield 17.3 g of the dicyclohexylamine salt of the title compound as a nearly colorless solid of mp 148 to 153 ° C. By recrystallization of the product from .125 ml of ethyl acetate 14.5 g of colorless Dxcyclohexylaminsalz be obtained, mp 157-159 ° C; [α] _β : -30 ° (c, 1% in ethanol).

analysis for C ₁ 0 17 ° 4 · ^C 12 ^H 23 ^N: N 07 C H 7, 06 About: 66 , 63 .10 ,1?.. 7, gef. : 66 , 47. , .10 , 22

For conversion into the free acid, 14.4 g of the dicyclohexylamine salt are pulverized, suspended in 100 ml of ethyl acetate and treated portionwise with 100 ml 10% potassium bisulfate solution. Thereafter, the organic phase is separated and the aqueous phase extracted twice with 100 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated. Yield 6.7 g (41%) of the title compound as a pale brown liquid. ,

c) (trans) -1 - [D- 3- (acetylthio) -2-methyl-1- oxopropyl ] -4- propoxy -L- proline

6.4 g (0.03 mol) of N-acetyl-trans-4-propoxy-L-proline are treated with a solution of 10 g of concentrated sulfuric acid in 100 ml of water. The resulting solution is refluxed for 3 hours and stirred. The solution is then cooled to 15 C, 12 g of sodium carbonate is added in portions to bring the pH to 8.0, and then with a solution of 5.4 g (0.03 mol) of D-3-acetylthio 2-methylpropionyl chloride in 5 ml of diethyl ether over 10 minutes, with 7 g of sodium carbonate being added to keep the pH at about 8.0, then the mixture is kept in an ice bath for 30 minutes and then at room temperature for 1 hour The product is then separated off and purified as the dicyclohexylamine salt according to Example 3. Yield: 6.3 g of the dicyclohexylamine salt of the title compound of melting point 165 ° -167 ° C. (from acetonitrile); [a] ^ ⁵ .: -5.6 ° (c, 1% in ethanol).

Analysis for C ₁₄ H ₂₃ NO ₅ S. C ₁₂ ^H ₂ 3 ^N:

- '

CH 'N S

Calculated: 62.62. 9.30 5.61 6.43

F .: 62.35 9.48 5.88 6.45

For conversion into the free acid, 6.1 g of the dicyclohexylamine salt are suspended in 60 ml of ethyl acetate, cooled in an ice bath and combined with 60 ml of 10% potassium bisulfate solution. Thereafter, the layers are separated and the aqueous phase extracted twice with 60 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and evaporated. Yield: 4.0 g (42%) of the title compound as a nearly colorless syrupy material.

Example 11

1- (D-3- mercapto-2- methyl -1-oxo-propyl ) -trans-4 -propoxy-, ' L-proline '.

According to Example 4, 4.0 g of (trans) -1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4-propoxy-L-proline with 8 ml of concentrated ammonia in 20 ml of water under argon hydrolyzed as a protective gas. There are obtained 3.42 g (97%) of the title compound as an almost colorless syrupy material;

: -72 ° (c, 1% in ethanol).

analys e for ^C 12 ^H 2 ^N O.S 5 • 1/4 I C ⁱ 2 ° H 5 N 1 S , 46 5 , 49 , 74 5 , 05 1 1 , 51 About: 1 , 66 7 , 76 , 94 O gef. : 1 7

Example 12

1 - (3- mercapto-1-oxo- propyl) -cis-4- methoxy-L-pr oli n

^a ) 1 ~ (3 - Acetylthio-1-oxo- propyl ) -cis -4-methoxy -L-proline According to Example 1 (d), cis-4-methoxy-L-proline is dissolved in the presence of potassium carbonate with a solution of 3 -Acetylthiopropylchlorid implemented. The Ti'telverbindung is obtained.

b) 1- (3-Mercapto-1-oxo- propyl) -cis -4-methoxy-L-proline According to Example 2, the 1- (3-acetylthio-1-oxopropyl) -cis-4-methoxy-L- Proline hydrolysed with an aqueous ammonia solution. It will get the title connection.

Example 13 (Ice) -4-Et'hoxy-i- (p -3 -mercapto-2-methyl-1-ox; Qp'ropyl) -L-proline.

a) ice-4-ΑίΙΐθχγ -ί-ρΓθ1ιη

Example 7 (a) to (d). is repeated with the change that instead of methyl iodide in part (b) ethyl iodide is used. It will get the title connection.

b) (ice) -1- [D-3- (acetyltio ) -2- methyl-i-oxopropyl] -4-ethoxy-L- proline

According to Example 7 (e), the (ice) -4-ethoxy-L-proline is reacted with a solution of D-3-acetylthio-2-methylpropionyl chloride in the presence of sodium carbonate. It will be the

Title compound obtained

 15

c) (ice) -4-ethoxy-y- (D ~ 3-mercapto-2-methyl-1-oxo-propyl) -L-proline

According to Example 8, the cis-1- [D-3- (acetylthio) -2-methyl-1-oxo-propyl] -4-ethoxy-L-proline is treated with an aqueous ammonia

hydrolyzed solution. It will get the title connection.

Example 14

(trans) ~ 4-yloxy AELL-1- (D-3-Mercap to ~ 2- met hyl-1-prop oxö yl) -L-proline

a) (trans) -4-allyloxy-L-pro- lin .

Example 1 (b) is repeated with the change that allyl bromide is used instead of methyl iodide. There is obtained the (trans) -N-acetyl-4-allyl-L-proline allyl ester, which is hydrolyzed according to Example 1 (c). It will be the

Title compound obtained.

b) (trans) -1 - [D-3- (Acet ylth io) -2-methyl-l-I -oxöpropyl] -4-allyloxy-L-pr olin

According to Example 3, (trans) -4-allyloxy-L-proline, which is

standing under a) was obtained with an equivalent Men

8 9 β

ge of D ~ 3 ~ (7 ^ cetylthio) -2-m.ethylpropionylchlorid implemented. It will get the title connection.

c) (trans) -4-allylox y-i, - (DHS-mercapto [3 -methyl-1- oxopropyl) L-proline

According to Example 4 is the: (trans) - 1; - [. D-3 .- (acetylthio) ~ 2 ~ methyl-1-o.xopropyl] ^ 4-a.llylaxy-L-proline with. hydrolyzed an aqueous ammonia solution. It will receive the Titelverbindurig.

Example 15

1- (D-3 -mercapto-2-methyl-1-oxoproyl ) -trans-4- . , propargyloxy-L-proline

a) (trans) -4-propargyl.oxy -L-proline ...

Example 1 (b) is repeated with the modification that propargyl bromide is used instead of methyl iodide. The (trans) -N-acetyl-4-propargyl-L-proline-propargyl ester is obtained, which is hydrolyzed according to Example 1 (c).

It will get the title connection. 20

^b ) (trans) -1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -4- per pargyloxy-L-proline

According to Example 3, the (trans) -4-propargyloxy-L-proline obtained in (a) above is reacted with an equivalent amount of D-3- (acetylthio) -2-methylpropionyl chloride. It will get the title connection.

c) 1- (D-3-mercapto -2-methyl-1-oxopropyl) -trans-4-propargyloxy-L-proline

According to Example 4, the (trans) -1- [D-3 ~ (acetylthio) -2-methyl-1-oxopropyl] -4-propargyl-L-proline is hydrolyzed with an aqueous ammonia solution. It will get the title connection.

& ° '' "" "35 _

Example 16

(trans ) ^ -benzyloxy y-T- (p ~3 ^: mercapto-2-methyl-1-oxypropyl) -L-proline.

a) ' (trans) -4- Benzyloxy-L-proline .

Example 1 (b) is repeated with the change that benzyl chloride is used instead of methyl iodide. There is obtained the (trans) -N-acetyl-4-benzyloxy-L-proline benzyl ester, which is hydrolyzed according to Example, 1 (c). It will get the connection!

 10

b) (trans) -1 - [D-3- (acetylthio) -a-methyl-i-oxopropyl] -4-.

benzyloxy -L-proliri ^:.

According to Example 3, the (trans) -4-benzyloxy-L proline obtained in (a) above is reacted with an equivalent amount of D-3- (acetylthio) -2-methylpropionyl chloride. It will get the title connection.

°) (trans ) -4-Benzyloxy-1- (D -3-m- ercapto-2-methyl-1-oxo- propyl) "L-proline

According to Example 4, the (trans) -1- [D-3 - (. Acetylthio) -2-methyl-1-oxopropyl] -4- ~ benzyloxy-L-proline is hydrolyzed with an aqueous ammonia solution. It will get the title connection.

Example 17 1 - (D-3-mercapto-2 -methyl-1-oxoprgyl) -trans-4-phenethyl - l-proline

a) (trans) -4-

Example 1 (b) is repeated with the change that instead of methyl iodide, phenethyl bromide is used. There is obtained the (trans) -N-acetyl-4-phenethyloxy-L-proline phenethyl ester, which is hydrolyzed according to Example 1 (c). The title connection is obtained.

.35 b) (trans) -1 - [D-3- ( acetylthio) -2-methyl] -1 -oxypropyl] -4-

pheriäthylox y-L-prol in.

According to Example 3, the (trans) -4 (a) prepared according to (a) is

L _J

§ # - 37 -

Phenethyloxy-L-proline in an equivalent amount. D ~ 3- (acetylthio) -2-methylpropionylchlorid reacted. The title compound is obtained.

c.) 1 - (D-3 ~ mer capto-2-methyl ~ 1-oxo propyl) -trans-4-phen- 'eth yloxy ~ ~ L proline

The (trans) -1- [D- (acetylthio) -2-methyl-1-oxopropyl] -4-phenethyloxy "L-proline is hydrolyzed with an aqueous ammonia solution as in Example 4. The title compound is obtained.

Example 18

1 ~ (D-3-mercapto-2-methyl-1-oxopropyl) -is-3-methoxy-L- proline

a) 1 - [D-3- (acetylthio) -2- methyl- 1-oxo-propyl ] -is-3-.

methoxy-L-proline

Example 7 is repeated with the modification that, instead of (ice) -4-methoxy-L-proline, an equivalent amount of (ice) -3-methoxy-L-proline (J. Amer. Chem. Soc. 85 (1963) .

s. 3863) is used. It will get the title connection.

b) 1 - (D-3-mercapto-2-methyl-l -oxo-1 pro pyl) -cis-3-methoxy-L-proli n

According to Example 4, the 1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -is-3-methoxy-L-proline is hydrolyzed with an aqueous ammonia solution. It will get the title connection.

Example 19 1- (D, L-3-mercapto-2-methyl-1-oxopropyl) -tr ans-3-methoxy-L- proline

a) .1- [D, 1-, 3- (acetylthio) -2-methyl-1-oxopr- opyl] -trans-3

According to Example 3, equivalent amounts of (trans) -3-methoxy-L-proline (JVAmer, Chem. Soc., 85, (1963), p. 3863) and D, L-3- (acetylthio) -2-methylpropionyl chloride implemented.

r - |

"" "'- 38 - The title connection is obtained.

b) 1 - (D, L-3-mercapto-2-methyl -1-propyl ) -trans-3

itiethoxy-L-proline,.

According to Example 4, the 1- [D, L-3- (acetylthio) -2-methyl-1-oxopropyl] -trans ^ 3-methoxy-L-proline is hydrolyzed with an aqueous ammonia solution. It will get the title connection.

B ic ρ ie 1 20 1 - (D-3-mercapto -2-methyl- 1-oxo- per- pyl) -cis-4- methylthio- L-pro! in

a) 1- [D-3- (acetylthio) -2-m ethyl-1 -oxopropyl] -cis-4- methylthio-Lp rolin

According to Example 3, equivalent amounts of (eis) -A- methylthio-L-proline (J.Amer.Chem.Soc., 79 (1957), p. 185) and D-3- (acetylthio) -2-methylpropionyl chloride are reacted , It will get the title connection.

b) 1- (D-3- mercapto-2-fluoro-1-oxopropyl) -cis-4-methylthio- L-proline

According to Example 4, the 1- [D-3- (acetylthio) -2-methyl-ioxopropyl] -cis-4-methylthio-L-proline is hydrolyzed with an aqueous ammonia solution. It will get the title connection. ,

Example 21

1- (D-3- mercapto -2-methyl-1-oxo-propyl ) -trans-4- methylthio- L-proline n a) 1- [D-3 "(acetylthio) -2-methyl-T-oxopro pyl] -trans-4- methylthio-L-proline

In accordance with Example 3, equivalent amounts of (trans) -4-methylthio-L-proline (J. Am. Chem. Soc, 79 (1957)., P. 185) and D-3- (acetylthio) -2-methylpropionyl chloride are reacted , It will get the title connection.

Do not

b) 1- (D-3-mercapto-2-ethyl-1-oxopropyl) -trans-4- methylthio-L-proline ,

According to Example 4, the 1 - [D-3 - (acetylthio) -2-methyl'-1-oxopropyl] trans-4-methylthio-L ~ p.rolin is hydrolyzed with an aqueous ammonia solution. It will get the title connection.

B e i s ρ i e 1: 22 '

1- (DS-mercapto-S- methyl-1-oxopyryl ) -is-4- (4- pentenylthio ) -L-proline

a) (Eis) -A- (4-pentenylthio) -L-proline According to Example 1 (b), reaction of (Eis) -N-acetyl-4-mercapto-L-prdlin (Chem. Pharm. Bull. 20, (1972), p. 543) with 5-bromo-1-pentene in acetone in the presence of silver oxide of the (ic) -N-acetyl-4- (4-pentenylthio) -L-proline-4-pentenyl ester, which is hydrolyzed according to Example 1 (c). It will get the title connection.

b) 1- [D-3- (Acetylthio ) -3-methyl-1-oxo- propyl] -cis-4 "(4-.

pentene ylthlo) -L-proline

According to Example 3, the (ice) -4- (4-pentenylthio) -L-proline is reacted with an equivalent amount of D-3- (acetylthio) -3-ethylpropionyl chloride. It will be the title

² ^ received binding.

^c Ϊ 1- (D-3-mercapto-3-methyl-1-1-oxoprop yl) -ei s-4- (4-p, ducks yl thio) -L-proline

According to Example 4, the 1- [D-3- (acetylthio) -3-methyl-ioxopropyl] -cis-4- (4-pentenylthio) ~ L-proline with an aqueous. hydrolyzed ammonia solution. It will get the title connection.

Γ "1

$ ψ & - 40 -

Be i s ρ i e 1 23

(t rans) -1 - [D-3- (acetylthio ) ~ 2-methyl-T "oxo-propyl-4- methoxy- L-proline- methyl ester.

A solution of the compound of Example 3 in diethyl ether is added with a slight excess of diazomethane. The resulting mixture is allowed to stand at room temperature and then evaporated. It will get the title connection.

Similarly, using the cis compound of Example 7, the (eis) -1- [D-3- (acetylthio) -2-methyl-1-oxopropyl-4-methoxy-L-proline methyl ester is obtained

Example 24 15

1,1 '- [ Dithiodi (1-D-3-mercapto-2-methyl-1-oxopro pyl)] - bis [(trans) -4- methylthiol -Lp roline].

A solution of the compound of Example 4 is dissolved in ethanol and treated with stirring with a solution of one equivalent of iodine in ethanol. By adding n-soda lime-20

ge the pH of the solution is maintained at 6 to 7. Thereafter, the solvent is distilled off and the residue obtained is extracted with ethyl acetate. After drying over magnesium sulfate, the solution is filtered and the solvent distilled off. It will get the title connection.

Similarly, using the cis compound of Example 8, the 1, 1 '- [dithiodi- (1 -DS-mercapto) -methyl-1-oxopropyl)] bis- [(ice) -4-methoxy- L-proline].

· '

Example 25

Sodium salt of (trans) -4-methpxy-1- (D-3-mercapto-2-methyl-L - - ( 1-oxo- propyl) -L-proline

A solution of 2.5 g of the compound according to Example 4 in 25 ml of water is mixed with 0.84 g of sodium bicarbonate and then freeze-dried. The title link will be obtained.

Similarly, at. Using the eis.-compound of Example 8, the sodium salt of the isomer of the title compound, obtained. ,

Example 26 1- (4-Mercapto-1-oxobutyl) -cis-4-ine- thoxy-L-proline a) (cis) -1- (4-acetylthio-1-oxpbutyl) -4-methoxy-L-proline The Reaction of an equivalent amount of (eis) -4-methoxy-L - .. proline with 4-acetylthiobutyric acid chloride according to Example 1 gives the title compound.

Jb) 1- (4-Mercapto-i-oxobutyl) -cis-4-methoxy-L-proline The title compound is obtained by hydrolysis of the compound obtained above in a) with aqueous ammonia solution according to Example 2.

Example 27

1- (L-3-mercapto- 2-ethyl-1-oxopropyl ) trans-4-methoxy-D-proline

^a ) (trans) - 1- (L- (3- acetyltio) -2-ethyl-i-oxopropyl] -4-

methoxy-D- proline

Example 1 is repeated with the change that. in part a) (trans) 4-hydroxy-D-proline instead of (trans) -4-hydroxy

L-proline is used. It becomes (trans) -4-methoxy-D-25

obtained proline, which is reacted according to Example 3 with L- (3-acetylthio) 2-ethylpropionylchlorid. It will get the title connection.

b) 1 ~ (L-3- mercapto-2-ethyl -1-oxopropyl) -tra ns-4-methoxy-D-proline

By hydrolysis of the compound obtained in (a) above with aqueous ammonia solution, the title compound is obtained.

""' - 42 -

Example 28

1 - (2-mercapto-1-quinol ) -t ^: rans-4-methoxy- L-proline

a) (trans) -1 - (2-acetyl -1-oxyethyl ) -4-methoxy- L-proline Example 1 is repeated with the modification that 2-acetylthioacetyl chloride is used instead of 3-acetylthiopropionyl chloride. It will get the title connection.

b) 1- (2- Mecapto-1-oxoethyl) -tran -4- methoxy- L-proline. By hydrolysis of the compound obtained in (a) above with aqueous ammonia solution according to Example 2, the title compound is obtained.

Example 29

1- (2-mercapto-1-oxoethyl ) -is- 4-methoxy-L-proline . .......

^a ) (ice) -1- (2-acetylthio-1-oxoethyl) -4-methoxy-L-proline. According to example 28, (ice) -4-methoxy-L-proline in the presence of sodium carbonate is mixed with a solution of 2- Äcetylthioacetylchlorid treated. It will be the title link

receive

 20

b) 1- (2- Mercapto-1-oxoethyl ) -cis-4-m ethoxy-L-proline The title compound is obtained by hydrolysis of the compound obtained above in (a) with aqueous ammonia solution

receive

 25

Example 30

1 · - (2-mercapto- 1-oxoethyl) -cis-4-meth ylthio- L-proline a) ( Eis ) -1- (2-acetylthio-1-oxoethyl) -4-methylthio-L-proline By reaction equivalent amounts of (ice) -4-methylthio-L-proline (J.Amer.Chem.Soc, 79 (1957), p.185) and 2-acetylthioacetyl chloride according to Example 1, the title compound is obtained.

b) 1 - (2 -Mercapto-1- oxypethyl-cis- methylthio-L-proline The title compound is obtained by hydrolysis of the compound obtained above according to (a) with aqueous ammonia solution according to Example 2.

"*" 4 ό ^mr *

B ic ρ ie 1 31 1 - (D-3-mercapto-3-methyl-T-oxo-propyl ) -cis- 4 - (4r-pentenylthio ) -L-proline .

a) (ice) -1- [D-3- (acetylthio) -3-methyl-1-oxypropyl-4- (4- pentynylthio) -L-proline .

By reacting (ice) -N, -acetyl-4-m.ercapto-L-proline in the presence of silver oxide with. 5-Chloro-i-pentyne in acetone according to Example 1 (b), the (ic) -N-acetyl-4- (4-pentynylthio) -L-proline-4-pentynyl ester is obtained. This connection

is then according to Example 1 (c) hydrolyzed to (ice) -N-acetyl-4 ~ (4-pentynylthio) -L-proline. By reacting this compound with an equivalent amount of D-3- (acetylthio) -3-methylpropionyl chloride according to Example 3, the title compound is obtained.

b) 1- (D-3-mercapto -3- methyl-1-oxopropyl ) -cis-4- (4- pentynyl-1-t- butyl) -L- ^ per 1 iη.

By hydrolysis of the compound obtained in (a) above with aqueous ammonia solution according to Example 4, the title compound is obtained.

Example 32

(Ice) -4-Benzylthio-1- (D, L-3-mercapto- 3-ethyl-1-oxo-propyl ) -L-proline.

a) (cis) -1- [D, L-3- (acetylthio) -3-ethyl-jl-oxo prop yl] -4-benzylthio-L-proline,

By reacting (ic) -N-acetyl-4-mercapto-L-proline with benzyl chloride in acetone in the presence of silver oxide according to Example 1 (b), the (ic) -N-acetyl-4-benzylthio-L-proline benzyl ester, which is hydrolyzed according to Example 1 (c) to (ice) -N-acetyl-4-benzylthio-L-proline. This compound is reacted according to Example 3 with an equivalent amount of DvL-3- (acetylthio) valeroyl chloride. It will receive the Titelverbindurig.

OO '. ,

b) (cis). - 4 ^ Benzylthlp-T -. (, D _f L;. ^{-3-mercapto-3.-;} diethyl-1 - oxo propyl.) -L-prölin

By hydrolysis of the compound obtained in (a) above with dilute ammonia according to Example 4, the title compound is obtained.

Example 33

T, 1 '- [D ithiodi (1-D-3- mercapto-2-methyl-1- oxypropyl)] - bis [(trans) -4- methylthio-L-proline]

By reaction of the product obtained in Example 21 with iodine in ethanol according to Example 24, the title compound is obtained.

Example 34

(Ice) - I - [D-3 - (Benzoylthio) -2- methy1-1-oxopropyl] -4-methylthio-L-proline

DuAh reaction of equivalent amounts of (ice) -4-methylthio-L-proliri (J. Amer Chem. Soc, 79 (1957), p 185) and D-3- (benzoylthio) -2-methyl-propionyl chloride according to Example 3, the title compound is obtained.

Example 35

(trans) -1 - [D-3- (Phenyla cetyl) -2-oxopropyl} -A- m ethy1-1-methyl t hio-Ii-p rolin

By reacting equivalent amounts of (trans) -4-methylthio-L-proline (J.Amer.Chem.Soc, 79 (19.57), p.185) and D-3- (phenylacetylthio) -2-methylpropionyl chloride according to Example 3 obtained the title compound.

Example -36- ( Ice ) -4- ( 4-fluorophenoxy) -1- ( D3-mercapto- 2-methyl-1-oxopropyl) -L-proline

a) (Ice) -A- (4-fluorophenoxy ) -L-proline A solution of 8.4 g (O _f O24 mol) of N-carbobenzoxy-trans-4-hydroxy-L-proline benzyl ester (Baer et al ., Can. J.

Biochem. & Phys., 37 (1959), p. 583), - 4.0 g (0.036 mol)

L · .J

Γ '

4-Fluorophenol and 9.27 g (0.036 mol) of triphenylphosphine in 75 ml of anhydrous tetrahydrofuran is added dropwise over 1 hour with 6.2 g (0.036 mol). Diäthylazodicarboxylat added in 25 ml of tetrahydrofuran. Subsequently, the solution is stirred for about 15 hours at room temperature. The mixture is then added to the. Dry evaporated and the residue taken up with 100 ml of diethyl ether. Thereafter, the precipitated triphenylphosphine and Diäthylazodicarboxylat is filtered off. By column chromatography on silica gel, 8.1 g of a mixture containing about 70% N-carbobenzoxy-cis-4- (4-fluorophenoxy) -L-proline benzyl ester are separated. ,

A solution of 7.5 g of the benzyl ester-containing mixture obtained above is hydrogenated at a pressure of 1 atmosphere and room temperature with 0.8 g of 10 percent palladium on carbon. During the reaction, a colorless precipitate forms. After completion of the hydrogen uptake, the mixture is filtered and the

Filter cake leached three times with 125 ml of hot methanol. The methanol solutions are then evaporated to dryness. Yield: 3, -2 g of the title compound, mp 235-236 ° C.

Analysis for C _1n H ₁₀ FNO ^. 1/3 H "0: ^J 1112 3 2

C HN S

Cons .: 57.14 5.48 6.06 8.22

gef.i 56,94 5,19 5,94 7,97

k) 1 "[Ρ-3- (acetyltho ) -2 -methyl-1-oxo-propyl cis-4- (4- fluorophenoxy) -L-proline

A suspension of 2.25 g (0.01 mol) of cis-4- (4-fluorophenoxy) -L-proline in 125 ml of anhydrous pyridine is treated at room temperature with 1.0 g (0.01 mol) of triethylamine and 2 g of ( 0.011 mol) of D-3- (acetylthio) -2-methylpropionyl chloride. The mixture is then allowed to stand for about 15 hours at room temperature.

stirred temperature and then evaporated to dryness. The residue is taken up in water, covered with ether and acidified with 10% hydrochloric acid. Then the water layer is repeatedly extracted with diethyl ether. The combined diethyl ether layers are washed with water, dried over sodium sulfate and evaporated to dryness. There are obtained 3.9 g of residue, which is chromatographed on 250 ml of silica gel with diethyl ether as the eluent. This results in a fraction

containing the desired product. The column is washed with methanol and the wash liquid rechromatographed on a short silica gel column to obtain another batch of the product. This procedure is repeated again. Total yield: 1.2 g of pure title

,

connection.

c) (ice) 4- (4- fluorophenoxy) -1- (D -B-mercapto-1 -methyl-ioxo-propyl) -L-proline

1.2 g of the product obtained under (b) above becomes 20

dissolved in 25 ml of methanol and treated under argon as a protective gas for 40 minutes with 5 ml of concentrated ammonia. Thereafter, the volatiles are distilled off and the residue is overlaid with ethyl acetate. The water layer is acidified with 10% hydrochloric acid. The layers are then separated and the acidic layer washed with ethyl acetate. The combined organic layers are stripped twice with water and twice with saturated brine and then dried over sodium sulfate. Subsequently, the solvent is distilled off. Yield: 1.1 g of the title compound as a solid foamy residue.

analysis for C 15 ^H 18 FNO ₄ • 5 1 / 3 system. H ₂ O : 5 F S 60 C 5 H N 5 70 9 61 calc. • 54 , 05 ι 7Q , 4th _f 20 40 9 gef. 54 , 04 ι 71st 4 / 05

Thin-layer chromatography shows the product at the R value of 0.30 as detected by UV light, SH reagent (yellow spot) and vanillin (yellow spot) [a] p ⁵ : -80 ° (c, 1% in Chloroform).

Example 37 1- (3- Mercapto-1- oxopropyl) -cis-4-phenoxy-L-proline

a) (ice) -4-phenoxy -L-proline

Example 36 (a) is repeated with the change that an equivalent amount of phenol is used in place of the 4-fluorophenol. It will get the title connection.

b) 1- [3- (Acetylthio) -1-oxopropyl] -cis-4-phenoxy- L-proline According to Example 1, (ice) '- 4-phenoxy-L-proline is treated with a solution of S-acetylthiopropionyl chloride in Presence of sodium carbonate reacted. It will get the title connection.

c) 1 - (3-mercapto-1-oxop ropyl) -cis 4 ~ phenoxy-L ~ ~ ~ prol in · Hydrolysis of the compound obtained above according to (b) with aqueous ammonia solution according to Example 2 the title compound is obtained.

Example 38

1 - (D-3-mercapto-2-methyl-1-oxopropyl ) -cis-4- (4- methylbenzyloxy) -L-proline

Example 36 is repeated with the modification that instead of 4-fluorophenol in part (a) an equivalent amount of 4-methylbenzyialcohol is used. It will get the title connection.

Example 39 1 ~ (D-3-mercaptd ~ 2-methyl- 1-oxopropyl) -cis-4-p- ethyl- oxy-L-proline

Example 36 is repeated with the change that in part (a) instead of 4-fluorophenol an equivalent

1- 'Λι

Amount of phenethyl alcohol is used. It will get the title connection.

Example 40 1- (D-3-mercapto-2, -methyl-T-pxo- propyl) -cis-4- (3- methylthiophenoxy) -Lp roline

Example 36 is repeated with the change that in part (a) instead of 4-fluorophenol an equivalent amount of 3-methylthiophenol is used. It will get the title connection.

Example 41

(Ice) -4- (4-Chloro- phenoxy- y) -1- (D- 3-mercapto -2-methyl-1-oxo- propyl) -L-proline Example 36 is repeated with the change that in part (a ) an equivalent amount of 4-c-chlorophenol is used instead of 4-fluorophenol. It will get the title connection.

Example -42 1- (2- Mecapto-1-oxoethyl) -cis-4- (4- metoxyphenoxy) -L-proline

a) (ice) -4- (4-methoxyphenoxy) -L-pr olin

Example 36 (a) is repeated with the change that an equivalent amount of 4-methoxyphenol is added instead of 4-fluorophenol. It will get the title connection.

b) 1- [2- (acetylthio) -1-oxoethyl-cis-4- (4-methoxyphenoxy) -L-proline

According to Example 1 (d), the (ice) -4- (4-methoxyphenoxy) -L-proline is reacted with a solution of P. acetylthioacetyl chloride. It will get the title connection.

c) 1- (2-mercapto -1-oxoethyl ) -cis-4- (4-methoxy- phenoxy) -L-.

Proline By hydrolysis of the compounds obtained according to (b) above

prölin

With aqueous ammonia solution according to Example 2, the title compound is obtained.

Example 43 (ice) -4- (4- fluorophenylthio) .- 1- (D-3-mercapto- 2-methyl-1-oxo- propyl ). -L-proline

Example 36 is repeated with the exception that in part (a), instead of 4-fluorophenol, 4-fluorophenyl mercaptan is used

becomes. It will get the title connection. 10

Example 44.

1- (D-3-mercapto-2-methyl -1-oxopropyl) -cis-4- phenylthio-L-proline

a) N-Carbobenzyloxy-cis-4-phenylthio-L-proline met hy ester 0.85 g. (0.037 mol) of sodium metal are dissolved in 40 ml of anhydrous ethanol, and with stirring with 3.7 ml (0 ^ 036 Thiophenol, followed by 7.5 g (0.017 mol) of N-carbobenzyloxy trans -4-tosyloxy-L-prolinitiate ethyl ester (J. Mer. Chem. Soc., 79 (1957), p. 191).

puts. The last-mentioned compound gradually goes into solution. Soon after, however, a solid product begins to separate. The mixture is stirred for 4 hours and then allowed to stand at room temperature for about 15 hours. Then most of the ethanol is recycled at

distilled off evaporator. The almost solid residue is stirred with 120 ml of dichloroethane and 60 ml of water. The layers are then separated, with some methanol being added to help break emulsions, and the aqueous phase is washed twice with another 60 ml of dichloromethane

extracted. The combined organic phases are washed with 100 ml of saturated brine, dried over magnesium sulfate and evaporated. Yield: 6.5 g (100%) of the title compound as a pale yellow viscous oil.

b) N- carbobenzyloxy-cis-4-phenyl- thio-L-proline 6.5 g (0.017 mol) of the compound obtained under (a) above

I 4öV ©

Compound is dissolved in 55 ml of methanol, portionwise at a temperature of -1. to. +4 ⁰ C with 13 ml (0.026 mol) of 2 η sodium hydroxide solution, stirred for 1 hour at '0 C and then allowed to stand for about 16 hours at room temperature. Then about half of the solvent is distilled off on a rotary evaporator, the cooled solution diluted with 100 ml of water, washed with 60 ml of diethyl ether (washing liquid discarded), covered with 70 ml of ethyl acetate, stirred, cooled and acidified with 4.8 ml of 1: 1 hydrochloric acid , After phase separation, the aqueous phase is extracted three times with a further 40 ml of ethyl acetate. The combined organic extracts are dried over magnesium sulfate and evaporated. There are obtained 5.9 g of a pale yellow viscous oil, which is dissolved in 30 ml of ethanol, treated with 1.9 g of cyclohexylamine in 3 ml of ethanol and diluted with diethyl ether to 330 ml. After the addition of seed crystals, the crystalline cyclohexylamine salt precipitates. After about 16 hours of cooling, 5.3 g of mp 148-151 ° C (sintering at 135 ° C) was obtained.

The yield is stirred with 1.5 g of the same product from an earlier experiment together with 200 ml of boiling acetonitrile and then cooled. Yield 6.3 g of colorless cyclohexylamine salt: from mp 152 to 155 C (sintering at 137 ° C) [a] ^ ⁶ : -24 ° (c, 1% in ethanol).

The Cyclohexylaminsalz is suspended in 25 ml of ethyl acetate, stirred and treated with 25 ml of η-hydrochloric acid. Two pure layers are obtained, which are separated. The aqueous phase is extracted three times with a further 25 ml of ethyl acetate. The combined organic extracts are dried over magnesium sulfate and the solvent is distilled off. Yield: 5.0 g (65%) of the title compound as a nearly colorless very viscous syrup.

c) (ice) -4-phenyl- tert- L-proline hydride.

4.9 g (0.014 mol) of N-carbobenzyloxy-cis-4-phenylthio-L-

£ 1 A © ψ © _ 51 -

proline are treated with 25 ml of hydrogen bromide in acetic acid {3O to 32%), · loosely, closed and stirred magnetically. After 1 sturid the orange-yellow solution is diluted to 250 ml with diethyl ether. The product precipitates as a heavy oil, which gradually crystallizes out upon addition of seed crystals, rubbing and cooling. The mixture is stirred for 1 hour in an ice bath, filtered off under nitrogen as a protective gas, washed with diethyl ether, suspended in fresh diethyl ether, cooled for about 16 hours and then filtered again. Yield: 3.2 g (77%)

the title compound as a colorless solid from F. 106 to K nol).

up to 109 ° C (sintering at 99 ° C) [a] ^ ⁶ : -3 ° (c, 1% in methane

d) 1- [D-3- (acetylthio) -2-methyl-1-oxopropyl] -cis-4-.

phenylthio-L-proline

According to Example 1 (d), 3.0 g (0.0094 mol) of (cis) -4-phenylthio-L-proline hydrobromide and 2.0 g (0.011 mol) of D-3-acetylthio-2-methylpropionyl chloride in 25 ml of water, using about 15 ml of 20% sodium carbonate solution to maintain the pH at 8.0 to 8.4. There are obtained 3.8 g of a pale yellow viscous oil. By reaction with 1.8 g of dicyclohexylamine in 30 ml of ethyl acetate, 2.9 g of Dicyclohexylamxnsalzes (isolated in two batches) from mp 184 to 18.8 ° C (sintering at 180 C). Subsequent digestion with 15 ml of acetonitrile gives 2.4 g of colorless solid dicyclohexylamine salt, mp 184-186 ° C (sintering at 180 ° C), °; ⁶ : -75 ° (c, 1% in ethanol).

The dicyclohexylamine salt is treated according to Example 1 with 30 ml 10% potassium bisulfate solution and extracted with ethyl acetate. Yield: 2.0 g (59%). the title compound, as a glassy solid.

L j

r _ _;

e) 1 - (D -3-mercapto-2-methyl-1-oxopropyl) -cis-4-phenyl-butyl -L-proline

2.0 g (0.004 2 mol) of the compound according to (d) obtained above are treated according to Example 2 with 3.5 ml of concentrated ammonia in 8.5 ml of water, wherein the solid ammonium salt of the product separates from the reaction mixture. Yield: 1.35 g (100%) of the title compound as a viscous syrupy material, t ^a l _D ^: "" 4.3 (c, 1% in:

Ethanol).

Example 45

1 - (D-3- mercapto-2-methyl -1 -oxopropyl ) -cis-4- (4- chlorophenyl ) -yl-L-proline Example 44 is repeated with the modification that part

(A) an equivalent amount of 4-Chlorphenylmercaptan is used instead of thiophenol. It will get the title connection.

Example 46 1 - (D-3- mercapto-2-methyl -1-oxopropyl) -cis-4 - (3-trifluoromethyl-phenylthio) -L-proline

Example 44 is repeated except that in part (a), instead of thiophenol, an equivalent amount of 3-trifluoromethylphenyl mercaptan is used. It will get the title connection.

Example 47

(Ice) -4- (4-hydroxyphenylthio ) -1- (3- mercapto-1-oxopropyl) -Lproline

a) (ice) -4- (4-acetoxyoxyphenylthio ) -L -proline hydrobromide Example 44 (a) to (c) is repeated with the change that in part (a) instead of thiophenol an equivalent amount of 4- Acetyloxyphenylmercaptan is used. It

the title compound is obtained

 35

· ^Γ '*

Cf ii @) #l A ''

§S) .8 l | Cl pw - 53 -

b) (ice) -4- (4-acetyloxyphenylthio) -1- [3- (acetylthio) -1, -

oxoprop yl] -L-proline. _;

By reacting the above obtained in (a) compound with S-Acetylthiopropionylchlorid according to Example 1 (d), the title compound is obtained.

c) (ice) -4- (4-hydroxyphenylthio) -1- ( 3-mercapto-1-oxopropenyl)

propyl) -L - proline

By hydrolysis of the above obtained according to (b) compound with aqueous ammonia solution according to Example 2, the title compound is obtained.

Example 48

(Ice) -4-Benzyloxy- 1 - (D-3 -mercapto-2-ethyl-1-oxopropyl ) -I.-

proline .

Example 44 is repeated except that in part (a), instead of thiophenol, an equivalent amount of benzyl alcohol is used. It will get the title connection.

Example 49

(tr ans) -1 - (3-M ercapto-1-oxopropyl) -3-methylthio -D, L-proline ^a ) 1/2-dehydroproline-t-butyl ester A solution of 34.2 g (0.20 mol ) Proline tert-butyl ester

in 600 ml of diethyl ether at a temperature of -5 '

to 0 C while stirring dropwise over 10 minutes with 21.7 g (23.9 ml, 0.20 mol) of freshly prepared tert-butyl hypochlorite (Org. Syn., Coll. Vol. V, (1973), p. 184). During the addition, the temperature becomes -5

held to 0 C. After complete addition, the solution is stirred at this temperature for a further 5 minutes.

The vigorously stirred solution is treated rapidly (about 3 to 5 minutes) with a solution of 7.8 g (0.20 mole) of potassium in freshly distilled anhydrous (over Ca L ·) dried tert-butanol. After the addition, the temperature

ρ "1

temperature of the reaction mixture about 18 ° C. The reaction vessel is removed from the cooling bath and the mixture is stirred for 30 minutes. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. The residue obtained is in diethyl ether. taken and washed with several portions of water. Then the diethyl ether solution is dried and evaporated under reduced pressure. There are obtained 31.6 g of a yellow liquid which is mixed with a trace ^ O hydroquinone. The tube product is distilled. Yield: 22.4 g (66%). the title compound of bp. 60 to 62 ° C / O, 1 mm.

b) i-Benzyloxy- carbonyl-4,5-dihydro -IH-pyrrol-2-carboxylic acid ' t-butyl ester

A solution of 16.9 g (0.1 mol) of the compound obtained above under (a) in 70 ml of dichloromethane is cooled under argon as a protective gas to -10 ⁰ C and with a solution of freshly distilled benzyl chloroformate (14.2 ml; 0.1 mol, b.p. 62-64 ° C / O, 4 mm) in 70 ml of dichloromethane was added dropwise within 30 minutes. Thereafter, the reaction mixture is stirred for a further 30 minutes in the cold and then with a solution of 15.22 g (O _r 1 mol) of 1, 5-diazabicyclo [5.4.0] undec-5-ene in 70 ml of di-

chloromethane within 20 minutes. The cooling bath is then removed and the mixture is stirred at room temperature for 1 hour. The reaction mixture is then washed twice with cold dilute hydrochloric acid and once with saturated sodium carbonate solution and then evaporated under reduced pressure. Yield 18.2 g (60%) of the title compound as a pale yellow oil.

c) (trans) -i-benzyloxycarbonyl-S- methylthio-DyL-p roline- _;

t-buty lester.

A solution of 18.2 g (0.06 mol) of the compound prepared according to (b) above in 180 ml of anhydrous methanol

is added with cooling in an ice bath with 3.24 g (0.06 mol) of sodium methoxide. Then slowly methanethiol is introduced into the solution for 30 minutes. The reaction mixture is stirred for about 15 hours under argon as a blanketing gas at room temperature. The mixture is then diluted with dilute acetic acid. until the solution is slightly acidic. Now argon is passed through the solution for 1 hour, which is then evaporated to dryness under reduced pressure. The residue is with. Ethyl acetate, washed twice with saturated sodium carbonate solution, dried and concentrated under reduced pressure. Evaporated pressure. Yield: 17 g of yellow oil, which is purified by chromatography with 300 g of silica gel and petroleum ether and diethyl ether in a volume ratio of 4: 1 as the eluent. Yield: 11.1 g of the title compound as a colorless oil.

^ ^} (trans) -3-methylthio- D, L-proline 8.4 g (0.024 mol) of the compound obtained according to (c) above

20

Binding are reacted with 45 ml of 4 η hydrobromic acid in acetic acid. The mixture is stirred for 1 hour at room temperature and then evaporated under reduced pressure. The residue is mixed with a small amount of water and washed twice with diethyl ether. hereupon

25

The aqueous solution is placed on a column with 300 ml of ion exchange resin and eluted with water until the eluate is no longer strongly acidic. The product is then eluted at pH 6.5 (aqueous pyridine-acetate buffer). The ninhydrin-positive fractions are

30

agreed and lyophilized. Yield 3.4 g (88%) of white fluff. A small sample of this substance is made from methanol

35

recrystallized. The title compound, mp 196-200 ° C (Zers; Sint <analysis for CHO ₀ NS:

to 200 ° C (Zers, sintering at 192 ° C).

° 2 44 C. , H 8th N 1 9 S - '- ♦' About: 44 70 6 ₇ 88 8th , 69 1 9 , 89 gef. : , 53 7.10 , 61 95

e) (trans) -1 - [3- (acetylthio) -1-oxopropyl] -3- methyl-thio

D, L-proline '·.

3.05 g (0.019 mol) of (trans) -S.-methylthio-D 1 -L-proline are dissolved in 19 ml of 1 N sodium carbonate and diluted with 10 ml of water. The solution is then cooled in an ice bath and treated rapidly with stirring a solution of 3-Acetylthiopropionylchlorid in 20 ml of diethyl ether. The pH is kept at 8 by the addition of 1 η sodium carbonate. After 30 minutes, the pH remains constant after adding 45 ml of sodium carbonate solution. The layers are then separated and the aqueous layer washed once with diethyl ether. Then the aqueous layer is acidified with 10% sodium bisulfate solution and the product is extracted with ethyl acetate, dried and evaporated under reduced pressure. There are obtained 5.2 g of oil which are chromatographed on 150 g of silica gel with ethyl acetate as the eluent. Yield 3.85 g crude title compound.

A small sample is dissolved in diethyl ether and converted to the dicyclohexylamine salt, which is recrystallized from ethyl acetate. It will be the title compound from the 153 to 157 ° C it analysis for

up to 157 ° C

58 C 8th H N 1 S , 57. About: 58 , 44 8th , 53 5.83 1 3 , 74th gef. : / 77 , 57 5.68 3

f) (trans) -1 ~ (3- mercapto-1-oxopropyl) -3-methylthio-D, L-proline 2.05 g (0.007 mol) of (trans) -1- [3- (acetylthio) -I- oxopropyl] 3-methylthio-D, L-proline are cooled in an ice bath under argon as inert gas and treated with a saturated with cold argon mixture of 7 ml of water and 7 ml of concentrated ammonia. The resulting mixture is stirred for 30 minutes at 0 ° C and then acidified with hydrochloric acid. The product is extracted with ethyl acetate, dried and evaporated under reduced pressure. Yield 1.85 g, the Ste ~

19 6 _ 57 -

partially crystallize. Digestion with diethyl ether gives 1.0 g (57%) of a colorless, crystalline product. Recrystallization from 5. ml of ethyl acetate gives 0.85 g of the title compound, mp. 89-93 ° C.

analysis for C ₉ ^H 15 3 ^NS 2 ^: * » 43 C 6 H 5 N S 72 About: 43 35 6 , 06 5 , 62 25 , 91st gef. : 35 , 27 , 54 25

Example 50

(trans) -1- (D-3-mercapto-2-methyl-1-oxo prop yl) -3-ethylthio-D, L-proline.

a) (trans) -3-ethylthio -D, L-proline

Example 49 (a) to (d) is repeated with the change that an equivalent amount of ethyl mercaptan is used instead of methanethiol. It will get the title connection

 - «

b) (trans) - 1- [D-3- (Acetylthio ) -2-methyl-1-oxopropyl ] -3-ethylthio-D, L-proline

By reacting (trans) -2-ethylthio-D, L-proline and D-3-acetylthio-2-methylpropionyl chloride according to Example 3, the title compound is obtained.

c) (trans) -1- (D-3-mercapto- 2 -methyl-1-oxopropyl) -3-ethyl

thio-D, L-proline

By hydrolysis of the above obtained according to (b) compound with aqueous ammonia solution according to Example 4, the title compound is obtained.

B e i s ρ i e 1 51

(trans) -1- (3-mercapto-1-oxopropyl ) -3-phenyl- thio-D, L-proline Example 4: 9 is repeated except that an equivalent amount of thiophenol is used instead of methanethiol. It will get the title connection.

Example 52 (Ice) -4-Methoxy-1- (p-3- mecapto- 2-trifluoromethyl-1-oxopropyl) -L-proline

a) 3- (4-methoxy-bis-cyl) -thio-2-trifluoromethyl-propionyl- chloride

A neat mixture of 3.9 g of 1-T.rifluormethylacrylsäure and 4 _f 3 g of 4-methoxybenzylthio C is stirred for 1 hour at 100 to 110 ⁰ and then allowed to cool to room temperature. The resulting solid precipitate is recrystallized from cyclohexane. The 3- (4-methoxybenzyl) thio-2-trifluoromethylpropionic acid of mp 72 to 74 C is obtained. ,

By reaction of this acid with thionyl chloride, the title compound is obtained.

b) (cis) -4-Met hox y-1- [D-3 ~ (4-methoxybenzyl) thio-2-ethyl trifluorm l-1-oxopropyl] -L-proline

The 3- (4-methoxybenzyl) thio-2-trifluoromethylpropionyl chloride is reacted with (ice) -4-methoxy-L-proline to give the title compound.

c) (ice) -4-methoxy-1 - (D ~ 3-m- ercapto-2-trifluoromethyl-1-oxopropyl) -L-proline

The compound obtained in (b) above is mixed with trifluoroacetic acid and anisole and stirred under nitrogen as a protective gas. Then, the solvents are distilled off under reduced pressure. The title compound is obtained as a residue. , , ·.

Example 53

(trans) -4 -Methoxy-i- (D-3-mercapto-2- trifluoromethyl-1-oxopro pyl) -L-proline

Example 52 is repeated with the modification that the (trans) -4-methoxy-L-proline is substituted for the cis isomer. It will get the title connection.

r. ...

B e χ. s ρ i e 1 54

(trans) -4-ethoxy -i- (D ~ 3-mercapto-2-trifluoromethyl-1-oxypropyl) -L-proline .

a) SA cetylthio ^ -trifluoromethylpropionyl chloride

A mixture of thiolacetic acid and 2- (trifluoromethyl) -acrylic acid is heated in a steam bath for 1 hour and then stored at room temperature for 18 hours. Then the reaction mixture is distilled under reduced pressure. The 3-acetylthio-2-trifluoromethylpropionic acid is obtained.

By reaction of this acid with thionyl chloride, the title compound is obtained.

b) (trans) -4-ethoxy-i- [D-3- ( acetylthio) -2-trifluoromethyl - 1-oxoprop- yl] -L-proline

By reacting 3-acetylthio-2-trifluoromethylpropionyl chloride with trans-4-ethoxy-L-proline according to Example 3, the title compound is obtained.

c) (trans) -4-ethoxy-1- (D-3-mer capt o-2-oxop trxflu ormethy1-1 rop yl) -L-proline

By reacting the compound obtained in (b) above with aqueous ammonia solution according to Example 4, the title compound is obtained.

Example 55

1000 tablets containing in each case TOO mg of the sodium salt of 1- (D-3-mercapto1-oxopropyl) trans -4-methoxy-L-proline are prepared from the following constituents:

Sodium salt of 1- (3-mercapto-1-oxopropyl) -trans-4-methoxy-L-proline 100 g

Corn starch. 50 g

Gelatin. 7.5 g

microcrystalline cellulose (Avicel) · 25 g

Magnesium stearate. 2.5 g

- .60 -

The 1- (D-3-mercapto-1-oxopropyl) -trans-4-methoxy-L-

Proline salt and the corn starch are mixed with an aqueous solution of gelatin. The resulting mixture is dried and ground to a fine powder. Then the Avicel and then the magnesium stearate

mixed with the granules .. Then the resulting mixture in a tablet press to 1000 tablets containing each. 100 mg of active ingredient is pressed.

^ ⁰ example. 56-

According to Example 5.5 tablets are each containing 200 mg of 1- (D ~ 3 ~ mercapto-2-methyl-1-oxopropyl) trans-4-methoxy-L-proline produced.

Example.'. 57

1000 tablets containing in each case 200 mg of the sodium salt of 1- (D-3-mercapto-2-methyl-1-oxopropyl) -cis-4-methoxy-L-proline are prepared from the following constituents:

Sodium salt of 1- (D ~ 3 ~ mercapto ~ 2-methyl ~ 1-

oxopropyl) -cis-4-methoxy-L-proline 50 g

Lactose. 25 g

Microcrystalline cellulose (Avicel) 18 g

Cornstarch 15g

Magnesium stearate 2 g

The sodium salt of 1- (D-3-mercapto-2-methyl-1-oxopropyl) -cis-4-methoxy-L-proline, the lactose and Avicel are mixed and then mixed with the corn starch. The mixture is then mixed with the magnesium stearate. The dry mixture is compressed in a tablet press into 1000 tablets with a mass of 130 mg, each containing 50 mg of active ingredient. These tablets are coated with a solution of methylcellulose (Methocel E 15) which, as a dye, has a pigment containing yellow # 6.

L _J

- .61 -

Example 58 2 parts # 1 gelatin capsules each containing 100 mg of sodium salt, of 1- (D-3-mercapto ^ 2-methyl-1-oxopropyl) -cis-4-methoxy-L-pr-Qlin are treated with a mixture of the following Components filled.

Sodium salt of 1- (D-3 ~ M.ercapto-2

methyl-1-oxopropyl) -cis-4-methöxy-L-

proline 100 mg

Magnesium stearate 7 mg

USP lactose. , 193 mg

Example. 59

An injectable solution of the following composition is prepared:

(trans) -4-Methoxy-1- (D-3-mercapto-2-methyl-1-oxopropyl) -L-proline 500 g

Parahydroxybenzoic acid methyl ester 5 g

Parahydroxybenzoic acid propyl ester 1 g

Sodium chloride 25 g

Water for injection qs. 5 1

The active substance, preservatives and sodium chloride are dissolved in 3 liters of water for injection and then made up to 5 liters. The resulting solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials which are sealed with pre-sterilized rubber stoppers. Each vial contains 5 ml of solution at a concentration of 100 mg of active ingredient per ml of solution for injection.

According to Examples 55 to 59, the products of all examples can be formulated into drugs.

Claims (3)

Erfindungsanspjcuch ^ 1. A process for the preparation of mercaptoacyl derivatives of substituted prolines of the general formula I. h * 2 .R ₄ -S- (CH) -CH-CO-N C * -COOR '.. ^H:. and their salts with bases, wherein the radical XR ₁ in the 3- or 4-position of the proline ring is connected ge , and X is an oxygen or sulfur atom / R is a hydrogen atom or a lower alkyl radical, R 1 is a lower alkyl, lower alkenyl or lower alkynyl radical / an optionally substituted phenyl group or an optionally substituted phenyl-lower-alkylene radical / R 'and R "are independently hydrogen atoms or lower alkyl radicals _t -Trifluormethy! Groups, O Il R _{4 is} a hydrogen atom, the radical R -C- or the radical -S- (CH 2) 2 -CH 2 -CO-N -C COOR η ι * and R _{5 is} a lower alkyl radical, a phenyl group or a phenyl-lower-alkylene radical and η is 0, 1 or 2, L J , characterized in that a prolin derivative of the general formula II H ₂ C XR ₁ ΗΝ ™ (II) COOR in the X, R and R ₁ as defined above with a carboxylic acid derivative or its chemical equivalent of the general formula in. ''·. · ^R 3? 2 CH - COOH in which R ", R ₀ and η are as defined above and R ¹ ^. represents a hydrogen atom or the radical R-CO-, to give a compound of general formula I in which R _{4 represents} a hydrogen atom or a radical R ₅ -CO-, optionally the resulting "compound in which R 1 represents the radical R ₅ Is -CO-, hydrolyzed to a compound of general formula I in which R. is a hydrogen atom, for the preparation of the compounds of general formula I in which R _{4 is} the radical represents, the obtained. Compounds of general formula I in which R. represents a hydrogen atom, _f oxidized with iodine and optionally converting the obtained compounds of the general formula I with a base into a salt. r. .2 1 Ii? Φ . ₆₄ _ 2. The method according to item Ί, characterized in that 'reacting a compound of general formula II with a compound of general formula III Ver to a compound of general formula I, in the R _{4 is} a hydrogen atom or the radical Rc-CO. 3, Method according to item 1, characterized in that one hydrolyzes a compound of general formula I in which R _{4 is} the radical R ₅ "" CO, to give a compound of general formula I in which R _{4 represents} a hydrogen atom. , 4c. Process according to item 1, characterized in that, for the preparation of the compound of general formula 1, in COOR represents a compound of general formula I in which R _{4 represents} a hydrogen atom, oxidized with iodine. L -J