DD148338A5 - METHOD FOR PRODUCING KETAL AND THIOKETAL DERIVATIVES OF MERCAPOTACYLPROLINS AND PEPECOLINSAEURES - Google Patents

Abstract

The invention relates to a process for the preparation of ketal and thioketalderivaten of mercaptoacylprolines and -pipecolinsaeuren the general formula (formula) in which the radicals have the meaning given in the invention claim. These compounds are drugs that lower angiotensin-induced hypertension.

Description

-4- 2 1 806 1

Title of the invention:

"Process for the preparation of ketal and thioketal derivatives of mercaptoacylprolines and -pipecolic acids"

Field of application of the invention: 20-

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

Characteristic of the known technical solutions:

Publications which underlie the present invention as prior art are currently unknown.

Object of the invention:

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

Explanation of the essence of the invention:

The invention has for its object to provide new drugs for controlling high pressures, compared to conventional hypotensive agents by a

higher efficiency.

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The invention relates to processes for the preparation of ketal and thioketalderivaten of Mercaptoacylprolinen and ^ pipecolic acids of the general formula I.

R ₁ R ₂ II

I i

R - S- (CH) -C-C 5 "

N -

C-COOR

in the

R represents a hydrogen atom or a lower alkyl radical,

R ₁ and Rp independently of one another are lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl radicals or radicals of the general formulas

or

or R ₁ and R _? together a Polymethylenrest the general

my formula

35 yrs

mean,

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X ₁ , X ₀ and X _o independently of one another are oxygen or sulfur atoms,

Ro and Ru independently of one another are hydrogen atoms, lower alkyl, lower alkylthio, - (CH ₂ ) -SH- or halogen-substituted lower alkyl radicals,

Rg represents a hydrogen atom or a lower alkyl radical, with the proviso that Rg is a lower alkyl radical only if R ₁ also denotes a lower alkyl radical,

m is 0, 1 or 2, η is 1, 2 or 3,

ρ and q each have the value 1 or 2, with the proviso that not both have the value 2,

t has the value 2 or 3,

R "is a hydrogen atom, a C ₁ ^ .- alkyl, C ₁ ^ alkoxy, Cijj alkylthio group, a chlorine, bromine or fluorine atom,

Trifluoromethyl or hydroxyl group, 25

Rq and R _{10 are} both hydrogen atoms, both lower alkyl radicals or a radical thereof is a hydrogen atom and the other radical is a lower alkyl, halogen-substituted lower alkyl or hydroxyl-substituted lower alkyl radical

kylrest or a radical of the general formulas

- (CH 35

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mean,

R (- eiri hydrogen atom, a removable by hydrolysis or chemical protective group or, provided that neither R- nor R ^ is a radical of the general formula - (CH ₂ ) -SH, a sulfide of the general formula

-S- (CH) _m -C-C

"l

^(CH 2 ⁾ q

C-COOR

means, as well as salts of these compounds, characterized in that one

(1) a substituted proline or a substituted pipecolic acid of the general formula

HN

T ²

-X ₂

(CH ₂ )

COOR

with an acid of the general formula

• S-

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^R 4 ^R 3

I i

(CH) -C -COOH

^ra I

in which R 'represents a hydrogen atom or a protecting group removable by hydrolysis or by chemical means, or

(2) a compound of the general formula

^R5

0 Il / 1 \ (CH ₂ ) * H q COOR I ' I I R-

in the RV has the above meaning, with an alcohol or thiol of the general formulas

I ¹

implements,

or

to obtain a product in which R _{1 represents} a hydrogen atom or a protecting group removable by hydrolysis or by chemical means, optionally deprotecting to give a product in which R _{5 represents} a hydrogen atom, and optionally

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Products in which Rf- represents a hydrogen atom to form a product in which R _{5 is} a radical of the general formula

V h

S - (CH) _m -C-CO-N C * - COOR

^R 6 H

oxidized. ,

If R ₁ and R _? together form a polymethylene chain having or 3 carbon atoms, the corresponding cyclic ketals and thioketals can be represented by the following general formulas.

R ₁₀ . ^B 9 ^R 10 ^, ^R 9

Preferably, only 1 carbon atom of the polymethylene chain is substituted. ,

Within the meaning of R ₇ are as C. ^ alkyl, C, 2 alkoxy and C ₁ ^ .- alkylthio radicals, the radicals having in each case a carbon atom, ie, the methyl, methoxy or methylthio group is particularly preferred.

The stars included in the formulas given above indicate an asymmetric center in the ring.

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In the case of proline, i. if ρ and q each have the value 1, this center is in the L configuration ivor. In the case of pipecolic acid, i. if ρ and q each have the value 2, this center is in the D, L or L configuration.

^τ Asymmetric centers can also be present in the mercaptoacyl side chains, depending on the meaning of R, Rn and Rg. "Another asymmetric center can also be present in the ring if XiRi and Xp-Rp are different. Accordingly, the products may be in stereoisomeric forms or as racemic mixtures. All of these forms are included in the subject matter of the invention. In the synthesis explained in more detail below, the starting materials may be the racemate or one of the two enantiomers. When using a racemic starting material, the stereoisomers obtained as the end product can be obtained in the usual way by chromatographic methods or by fractional crystallization.

² ^ be separated. When an asymmetric center is present in the mercaptoacyl side chain, it is preferably in the D configuration.

The mercaptoacyl derivatives of proline and pipecolic acid of the general formula I which can be prepared according to the invention and the salts of these compounds are valuable active ingredients having an antihypertensive effect which can be processed to give corresponding medicaments.

The invention also provides processes for the preparation of certain intermediate products which serve as starting materials for the preparation of the compounds of general formula I. -

Means is used, - the term "lower alkyl group" of the definition of the radicals R, R _1, Rp, Rn ,, R- and R /

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^ straight-chain or branched radicals of hydrocarbons having up to 7 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and isopentyl group. Preference is given to lower alkyl radicals having up to 4 carbon atoms, the methyl and ethyl groups being particularly preferred. Similarly, the terms "lower alkoxy" and "lower alkylthio" refer to such lower alkyl groups to which an oxygen or sulfur atom is attached.

The term "cycloalkyl" refers to saturated rings of from 3 to 7 carbon atoms wherein the cyclohexyl-r

group is particularly preferred

 15

The term "halo-substituted lower alkyl" refers to the above-mentioned lower alkyl groups wherein 1 or more hydrogen atoms are substituted by chlorine, bromine or fluorine atoms. examples for

corresponding groups are the trifluoromethyl, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl and bromomethyl group.

The term "hydroxyl-substituted lower alkyl radical"

refers to the above-defined lower alkyl radicals in which a hydrogen atom is replaced by a hydroxyl group. Examples are the hydroxymethyl and 2-hydroxyethyl group.

The term "lower alkenyl" in the context of the radicals R and Rp means monounsaturated, straight-chain or branched hydrocarbon radicals having 2 to 7 carbon atoms, such as the Äthenyl-, Propenyl-, Isopropenyl- and

Butenyl. By the term "lower alkynyl" 35

are straight-chain or branched hydrocarbon radicals having 2 to 7 carbon atoms and a triple bond

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• to understand, for example, the propargyl group. Preference is given to lower alkenyl radicals having 2 to 5 carbon atoms and lower alkynyl radicals having 2 to 4 carbon atoms.

, , '' '-; The term "removable by hydrolysis protective group" in the definition of R, - means groups which can be removed by conventional hydrolysis or ammonolysis. Acyls are suitable for this purpose.

^ residues of the general formula _:

  - · o

• t. R ₈ -C-,

where Rg can have one of the following meanings: lower alkyl radical having 1 to 7 carbon atoms, lower alkyl radical substituted by 1 or more chlorine, bromine or fluorine atoms, - (CHp) -cycloalkyl radical, aryl radical, for example of the general formula

and heterocyclic radical, for example radicals of the formulas

or

^Λ 3

where r is 0.1, 2 or 3 and R ₇ and X ~ are as defined above. Preference is given to lower alkanoyl radicals having up to 4 carbon atoms, in particular the acetyl group, and the benzoyl group.

By the term "chemically removable protecting groups" in the definition of R, - are groups such as

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the p-methoxybenzyl, V p -methoxybenzyl

oxycarbonyl, trityl and tert-butoxycarbonyl group to understand. These groups can be removed after completion of the acylation reaction to various conditions depending on the importance of X-i-R-i and Xp-Rp, for example by treatment with trifluoroacetic acid and anisole, sodium and liquid ammonia or mercury (II) trifluoroacetate.

W Preferred compounds of general formula I are the L-proline derivatives, i. ρ and q are both 1 and R is hydrogen.

With regard to the mercaptoacyl side chain, as end products such compounds are preferred in which R _{1 is} a hydrogen atom, m is 0 or 1, R 1 is a hydrogen atom and R 1 and R 4 each are lower alkyl radicals 1 to 4 carbon atoms, in particular both a methyl group, mean, or in which Rg is a Wasser * ^u substance and R ^ is a hydrogen atom, a lower alkyl radical having 1 to 4 carbon atoms, in particular the methyl group, a trifluoromethyl, methylthio or mercaptomethyl group , Preference is also given to intermediates and end products in which

chain Rc is a lower alkanoyl radical having 1 to 4 carbon atoms, in particular the acetyl group, or a benzoyl group.

Particularly preferred end products are compounds of general

of the formula I having a mercaptoacyl side chain in which Rp represents a hydrogen atom, m is 1, R ₁ . and Rg represent hydrogen atoms, R-. is a methyl group and the asymmetric carbon atom to which the Rj is bonded is in the D configuration. ^ä

With regard to the substituents on the pro-ring, preference is given to those compounds in which R ₁ and R _{2 are} independent of each other.

2180 6 1

lower alkyl radicals having 1 to 4 carbon atoms,

in particular the methyl or ethyl group, or one ^; Remainder of the ⁵ general formulas. , *

or

and R "is a hydrogen atom, a methyl, methoxy or methylthio group, a chlorine, bromine or fluorine atom, a trifluoromethyl or hydroxyl group or X ₁ -R-] ^{un <} 3 X ₂ -Rp ^e: * - ^NEN Ri ⁿ S of the formulas

Ίο Ι

10

CH.

ι '

R ₁ H "C

10 CH.,

or

CH

 S

mean, wherein R. and R ₁₀ are both hydrogen or both lower alkyl of 1 to 4 carbon atoms, in particular both hydrogen atoms or both methyl groups, or R _q is a hydrogen atom and R is a lower _

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t is alkyl radical having 1 to 4 carbon atoms, in particular the methyl group, a hydroxyl-substituted lower alkyl radical having 1 to 4 carbon atoms, in particular the hydroxymethyl group, or a halogen-substituted lower alkyl radical, in particular the trifluoromethyl group.

With respect to the proline ring, such compounds are particularly preferred in which X ₁ and Xp are the same, and particularly those compounds in which X ₁ -R ₁ and Xp-Rp each represent methoxy groups or ethoxy groups or in which each of X ₁ - R ₁ and Xp-Rp together form radicals of the following formulas

CH, ./ ³

_H CH, HC - CH, HC CH,.

² II ^{2 2} III »

λ r »OO SS-

H, C CH

SS

The preparation of the compounds of general formula I is explained in more detail below:

A substituted proline or a substituted pipecolic acid of the general formula II

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? 2

/ ^c \

; HN C-COOR

  V '*' '..' I *:. '.

'-V ^:. '''''''.:': ··. ^Η ...''"'':' - '.''''V-

is with an acid or its chemical equivalent of the general formula IIP

r'-S- (CH) -C-COOH (III)

5 I

in which R'r is a hydrogen atom or a protecting group which can be removed by hydrolysis or by chemical means, with formation of a product of general formula IV

R ₁ ΚΙ ¹ I ²

ΐΐ / 2

^ C

(H ₀ C)

»4 f3 V.

R ^ S- (CH) ₁₅ - C- CO- N C-COOR

^! H

coupled.

This reaction may be carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide. Another possibility is the acid by education

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a mixed anhydride, a symmetrical anhydride, an acid halide, an active ester or using Woodward's reagent K, N -ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or the like. An overview of such acylation is found in Houben-Weyl, Methods of Organic Chemistry, Vol. XV, Part II (1974), p. 1 ff .. Preferably, the acid. halide, in particular the acid chloride, the general formula III reacted with the acid of general formula II.

When the proline or pipecolic acid of general formula II is reacted in the ester form, the resulting ester of general formula IV, i. R represents an alkyl radical, which is converted into the free acid by conventional methods, ie. R represents a hydrogen atom, to be converted. For example, when R represents an ethyl group, this ester protecting group can be removed by saponification.

The product of general formula IV is preferably isolated and purified by crystallization, for example by forming the dicyclohexylamine salt and then converting this salt into the free acid by treatment with an aqueous solution of an acid such as potassium hydrogen sulfate.

Products of general formula IV, which have an acyl radical of the general formula Rn-CO-, can by conventional hydrolysis or ammonolysis in products of the general

Formula I, in which R ^ represents a hydrogen atom, are transferred.

The products of the general formula I, in which R 1 and R ₁ , are not radicals of the general formula - (. CH ₀ ) -SH and

" ⁿ

in the R ^ a radical of the general formula

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, is

i fa

s ²

^R 3 ^{H 2 ^C) P ^(CH 2 ^J a-)

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

^m , * I

.. · .. tt. ' ^H. ·.: · · · -. "

. '. · .- />. :, ^: . ' ⁶ . . '. ^: · ^{; /} . -. \

are obtained by directly oxidizing a product of general formula I, in which R ₁ - a hydrogen atom, with iodine.

The esters of general formula I in which R represents a lower alkyl radical can be prepared from the corresponding carboxylic acids, i. R denotes a hydrogen atom, prepared by conventional esterification processes, for example by esterification with a diazoalkane, such as diazomethane, an i-alkyl-3-p-tolyl triazene, such as i-n-butyl-3-p-tolyl triazene, or the like. ·

The disubstituted prolines or pipecolic acids of the general formula II in which X ₁ -R ₁ and X ₂ RP have the same meaning, can be obtained by reacting a N-protected keto compound of general formula V

II

(H ₂ C) _p (CH ₂ ) _q (V)

Cbz N Cr-COOR

^H '·''..' 35

in which Cbz represents the carbobenzyloxy group, with a

- 16 - 2 1 80 6 1

Alcohol or thiol of the general formula VI

R ₁ -X ₁ -H (VI)

in the presence of an orthoformic acid ester or orthothioic acid ester of the general formula

HC (X | -R ₁ ) ₃

and an acid such as concentrated sulfuric acid or p-toluenesulfonic acid. This reaction may be carried out in an inert organic solvent such as benzene, acetic acid, diethyl ether or cyclohexane, preferably with heating, for example to the reflux temperature; see. Buehler et al., Survey of Organic Syntheses, Wiley & Sons, 1977, Vol. 1, pages 516 to 519. The product of this reaction is the N-protected intermediate of general formula VII

RR

(H ₂ C) _p (CH ₂ ) _q

- N C-COOR

I * (VII)

The N-protected intermediate of general formula VII may be reacted with one molar equivalent of an alcohol or thiol of general formula VIII

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R ₂ -X ₂ -H (VIII)

are treated according to the conditions described above, to obtain the intermediate of general formula IX.

X ₁ X ₉ ^ C

(H ₂ C) _p . (CH ₂ ) _g

_cbz _ _N C-COOR

^H

When using a molar excess of the alcohol or. Thiols of the general formula VIII are obtained as an intermediate of the general formula X 20

X ₂

CbZ N-Cj-COOR _(x)

Afterwards, the N-protective group can be

be removed, for example, if X ₁ and X _n

both oxygen atoms mean by hydrogenation of the presence of palladium-on-carbon or if one or both of X ₁ and X _? Mean sulfur atoms, by

Treatment with HBr and acetic acid. This gives the disubstituted compounds of the general formula

, 18 -

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Similarly, the spiro compounds of general formula II, ie R ₁ and R _? are linked together in a polymethylene chain, by reacting the keto compound of general formula V with the alcohol or

Thiol of general formula XI;

• V _/ ^R io

; (c) _t ",

/ \ (XI)

I ¹ I ²

H * H

in which Rq, R ₁₀ and t have the abovementioned meaning, in the presence of an acid, such as p-toluenesulfonic acid. This produces the intermediate of general formula XII '

/ ^C \ _%

(H ₂ C, _p <CH ₂ ) _q

Cbz-N ·C-COOR (XII)

'I *

H '

Another possibility is the disubstituted zu.behandeln compound of general formula VII directly with a molar excess of the alcohol or thiol of the general formula XI to afford an intermediate *

product of general formula XII. This method is particularly useful when the radicals Rq

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and R 'Q either either or neither means a hydrogen atom.

'>! : '': '. ": -

Λ '

As explained above, the N-protecting group can then be removed, giving the spiro compounds of general formula II.

According to another procedure, the introduction of the radicals Xi-Ri and X ₂ -R ₂ can take place in a later stage of the process. According to this embodiment, the protected ketol compound of the general formula V is treated to remove the protective group. for example, with hydrogen bromide, whereby an intermediate of the general formula XIII

, ο

• H

H N C ^ COOH

H (XIII)

which is then acylated with the acid, preferably with the acid halide, the general formula III, whereby a compound of general formula XIV

i!

Ri-S- (CH) C C-N-C-COOH (XIV)

_ItI. '

5 H

- 20 - 21 80 6 1

receives.

The radicals X ₁ -R-. and X ₃ = R ₂ or the spiro test S " ^ ^C * £

/ ^R 10

may be introduced at this point according to the procedures outlined above to give a product of JO general formula IV.

With respect to the preparation of the starting materials and the intermediates, reference is also made to the following references: U.S. Patents 4,046,889, 4,105,776, 4,154,935 and 4,116,962, Can. J. Biochem. & Physiol., Vol. 1959), p. 584; JACS, Vol. 79 (1957), p. 189; J. Med. Chern., Vol. 21 (1978), p. 445; Aus. J. Chem., Vol. 20 (1967), p to 1509; Buehler et al., Survey of Organic Syntheses, Wiley & Sons, 1977, Vol. 1, pp. 516 to 519, Vol.

2, pp. 461-470; Chem. Pharm. Bull., Tokyo, Vol. 26 (1978), p. 2209 and 2217; Can. J. Chem., Vol. 47 (1969), p. 860; J. Amer. Chem. Soc., Vol. 80 (1958), p. 6350; Harrison et al., Compendium of Organic Synthetic Methods, Wiley-Interscience, New York, 1971, pp. 449-456; J. Amer. Chem. Soc., Vol. 79 (1956), p. 192; Bull.

Soc. Chem., 1965 (8), pp. 2253 to 2259; and J. Org. Chem., Vol. 25 (1960), pp. 521-530.

The methods described herein can be used as general methods for the synthesis of compounds and for the separation of isomers which can be used according to the invention. Additional details can be found in

the following examples, which can serve as a model method for the preparation of other members of the respective compound groups. '

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The compounds of the invention form salts with a variety of inorganic or organic bases. The following are examples of metals and amines from which the salts may derive: aluminum, alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, amines such as aralkylamines, e.g. Dibenzylamine and * N, N-f) ibenzylethylenediamine, lower alkylamines, e.g., methylamine and tert-butylamine, procaine, lower alkylpiperidines, e.g. N-ethylpiperidine, cycloalkylamines, e.g. Cyclohexylamine or dicyclohexylamine, 1-adamantanamine and benzathine. Furthermore, the salts may also be derived from amino

it . ·. -,. , derived acids such as arginine or lysine. The physiologically acceptable salts, such as the sodium or potassium salts, can be used for the medical purposes discussed below, and are therefore preferred These and other salts, which need not necessarily be physiologically acceptable, are suitable for isolation and purification for the following This is illustrated in the examples of the dicyclohexyl

amine salt explained. The salts are prepared by reacting the compound in the acid form with an equivalent amount of the base yielding the desired cation in a medium in which the salt precipitates or in an aqueous medium followed by lyophilization.

The free acid can be obtained by customary neutralization processes from the salt, for example with potassium hydrogen sulfate or hydrochloric acid.

«The compounds of general formula I, in which R, - a ->

Hydrogen atom, a radical of the general formula

or the disulphide-type substituent, and in particular the compounds in which R _{K is} a hydrogen

-22- 2180

atom means valuable substances with hypotensive effect. They inhibit the conversion of the decapeptide angiotensin I to angiotensin II and are therefore valuable drugs for reducing angiotensin-related high pressure. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in the blood plasma, produces angiotensin I. · Angiotensin I is converted to angiotensin II by the angiotensin converting enzyme (ACE). The latter product is an active hypertensive substance which is causally associated with various forms of hypertension in various mammals, such as rats and dogs. The compounds of the invention intervene in the reaction sequence angiotensinogen ^ (renin). Angiotensin I (ACE). Angiotensin II by inhibiting the angiotensin converting enzyme and reducing or completely preventing the formation of the hypertensive substance angiotensin II. Thus, by administering an agent containing one or more compounds of general formula I,

tensin-dependent hypertension in mammals. A single dose or preferably 2 to 4 doses distributed throughout the day, with daily doses of from about 0.1 to 100 mg per kg of body weight, and preferably from about 1 to 15 mg per kg of body weight, are maintained

Lowering blood pressure. The agents are preferably administered orally. However, parenteral administration may also be used, for example by subcutaneous, intramuscular, intravenous or intraperitoneal routes.

The compounds of the invention may also be formulated together with a diuretic for the treatment of hypertension. A combination product containing a compound of the invention and a diuretic may be administered to mammals of 70 kg body weight in total daily doses

from about 30 to 600 mg, and preferably about 30 to 300 mg

For the compound of the invention and from about 15 to 300 mg and preferably about 15 to 200 mg for the diuretic. Examples of diuretics which may be used together with the compounds of the invention are thiazide diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroglumethiazide, benzsidrofiumethiazide, methychlorothiazide, trichloromethiazide, polythiazide and benzothiazide, as well as etacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetariide, triamterene, amiloride and spironolactone and salts of these compounds. .

The compounds of general formula I may be compounded into appropriate dosage forms, for example tablets, capsules or elixirs for oral administration or sterile solutions or suspensions for parenteral administration, about 10 to 500 mg of a compound of general formula I or a mixture of such compounds are together with '

pharmacologically acceptable excipients, diluents, binders, preservatives, stabilizers, flavoring agents and the like are processed to a unit dose, as is conventional per se in pharmaceutical practice. The amount of active substance in such an

The parameter is chosen to correspond to the aforementioned dosage range.

EXAMPLES

on; '·

    .- Example 1

Γΐ (S), 8S 7-7- (Acetylthio ') - 2-methyl-1-oxopropyl 7-1. 4-dioxo-7-azaspiro / 4. * t / nonane-8-carboxylic acid a) N-carbobenzyloxy-4-hydroxy-L-proline 26.5 g (0.20 mol) of 4-hydroxy-L-proline and 32.8 ml (0.23 mol) of benzyl chloroformate are dissolved in 200 ml of water

^Γ - ^ - 21806 1

* and 100 ml of acetone in the presence of 20 g (0.02 mol) of potassium bicarbonate and 69.2 g (0.50 mol) of potassium carbonate and worked up with 90 ml of concentrated hydrochloric acid; see. Can. J. Biochem. & Physiol., Vol. 37 (1959), p. 584. N-carbobenzyloxy-4-hydroxy-L-pr-Qlin is obtained. This product is reacted with cyclohexylamine. This gives 69 g of cyclohexylamine salt of mp 193-195 ° C. 34 g of this salt are neutralized with 1 η hydrochloric acid. 27 g of the free acid are obtained in the form of a colorless glass. / Ix 7 ^ ⁶ = -70 ° (c = 1%, chloroform).

b) N'-Carbobenz.yloxy-il-keto-L-proline

21.5 g (0.81 mol) of N-carbobenzyloxy-4-hydroxy-L-proline are dissolved in 1.2 liters of acetone with 83 ml of 8% chromic acid in sulfuric acid.

ferric acid according to J.A.C.S., Vol. 79 (1957), p. 189. In order to facilitate the subsequent filtration of the chromium salts, 30 g of diatomaceous earth (celite) are added to the acetone solution before the oxidizing agent is added. For the reaction, an air stirrer is used. The reaction mixture is then filtered. The acetone filtrate is concentrated to a volume of about 300 ml and then diluted with 1 liter of chloroform. The solution is washed 4 times with 300 ml of saturated sodium chloride solution, dried over MgSCv and filtered off. After evaporation of the solvent to obtain 22.8 g of N-carbobenzyloxy-4-keto-L-proline, which is crystallized from 50 ml of ether and 150 ml of hexane. This gives 17.2 g (81 percent of th.) Of product from F. 99 to 101 °. ·

/."""""/Β ⁶ = ⁺ 17 ° "(c = 1%, chloroform).

c) N-carbobenzyloxy-4,4-ethylenedioxy-L-proline

A mixture of 12.8 g (0.049 mol) of N-carbobenzyloxy-4-keto-L-proline, 53 ml (0.095 mol) of ethylene glycol and 0.35 g of p-toluenesulfonic acid. HpO in 1.31 liters of benzene is heated with stirring. The resulting solution is allowed to stand for 7 hours

218 0 6 1

Reflux heated, the water formed is collected in a Dean-Stark apparatus- The mixture ³ WiTd ** left overnight at room temperature. The lower glycol phase is separated and the benzene solution washed with 150 ml of saturated sodium chloride solution, dried over MgSO ₁₁ and evaporated. This gives 14.6 g of N-carbo-bobeazyloxy-iljM-ethylenedioxy-L-proline as a syrupy residue. This residue is dissolved in 60 ml of ethanol, filtered, treated with 5 g of cyclohexylamine and diluted with diethyl ether. After seeding and rubbing, the crystalline cyclohexylamine salt separates out. After standing in the cold, 9.0 g of product are obtained, mp 179 ° -180 ° C. (sintering 173). The product is recrystallized from acetonitrile, whereupon the melting point is 182 ° -184 ° (sintering 179 °).

DxJ ^ = - ²¹ ° (c = ¹ %, ethanol).

8.4 g of the Cyclohexylaminsalzes are suspended in 40 ml of ethyl acetate with stirring and cooling and treated with ml 1 η hydrochloric acid. After separating the phases

^ O, the aqueous phase is extracted 3 times with 40 ml of additional ethyl acetate. The combined organic layers over MgSO _1, dried. The solvent is evaporated off, the final pressure being 0.2 torr. The syrupy residue obtained begins on the

** rub in diethyl ether to crystallize. After evaporation of the diethyl ether to obtain 6.4 g (42 percent of th.) N-Carbobenzyloxy-4,4-ethylenedioxy-L-proline in the form of a nearly colorless product of F. 101. to 103 ° C (sintering 98 ⁰ C).

Γα ti: ⁶ = -34 ° (c = 1%, CHCl ₃ ).

d) 4,4-ethylenedioxy-L-proline

A solution of 3.2 g (0.0104 mol) of N-carbobenzyloxy-4,4-ethylenedioxy-L-proline in 100 ml of methanol / water (2: 1) is treated with 1 g of 5% palladium-on-carbon and

Γ

- ²⁶ - 21 SO 6 t Shaken for 6 hours in a Parr hydrogenator. The catalyst is filtered off under nitrogen and washed with methanol. The combined filtrates are evaporated, the pressure being 0.1 to 0.2 Torr at the end. This gives 1.7 g (94 percent of th.) Of 4,4-ethylenedioxy-L-proline as a colorless solid from F. 245-247 ° C CZers.).

_T 26 -jo ° (° = 0.5%; 1: 1 methanol / water). .L ⁰ ^ ⁷ D ⁼ ~ ^{5 <L}

e) / ~ 7 (S), 8S 7-7- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl-7-1- (dioxo) -azaspiro / 4.4 / nonane-8-carboxylic acid

A solution of 3.2 g (0.0185 mole) of 4,4-ethylenedioxy-L-proline in 50 ml water is cooled with stirring to 5 ° C and brought to pH 8.5 by the portionwise addition of solid sodium carbonate ™ , Subsequently, with continued stirring and cooling, a solution of 3.7 g (0.020 mol) of D-3-acetylthio-2-methylpropanoylchlorid in 5 ml of diethyl ether added in portions, wherein the pH by addition of 25 percent sodium carbonate solution (about 14 ml ) is kept at 8-5. After 1 1/4 hours, the solution is treated with 50 ml of ethyl acetate, stirred, cooled, carefully acidified with hydrochloric acid (1: 1) to pH 2.0 and saturated with sodium chloride. After separating the phases, the aqueous phase is added 3 times with 50 ml each.

extracted additional ethyl acetate. The combined organic layers over MgSO _1, dried. The solvent is evaporated off, the final pressure being 0.2 mm. The solid residue is triturated under diethyl ether. The AbdampfVorgang is repeated. This gives 5.9 g (100 percent of Th.) Γΐ (S), 8sJ7-7- ^ f ~ 3- (acetylthio) -2-methyl-1-oxopropyl_7-1,4-dioxo-7-azaspiro _ / _ 4.4 __ / nonan-8-carboxylic acid of mp 108 to 111 C.

This product is mixed with 3.4 g of dicyclohexylamine in 70 ml

Ethyl acetate into the dicyclohexylamine salt.

218 0 61

* leads. After inoculating and rubbing the crystalline salt precipitates. Recrystallization from 95 ml of acetonitrile gives 6.7 g of product, mp. 187-169 ⁰ C (sintering 184 ° C).

.- -7-25 c-oo (c = 1%; ethanol)

Lo <J _O = -59. _

, , '· · . The dicyclohexylamine salt is converted into the free acid.

, ₄ leads by suspending it in ethyl acetate and treated with 75 ml of 10 percent potassium bisulfate solution and stirred until 2 phases are formed. After separating the phases, the aqueous phase is extracted 4 times with 75 ml of ethyl acetate. The organic phases are combined and concentrated over MgSO 4. dried. After evaporation of the solvent, 4.1 g of ΓΊ (S), 8S_7-7 -Ji 3- (acetylthio) -2-methyl-1-oxopropyl _ / - 1,4-dioxo-7-azaspiro _ / _ 4.4_ / nonane-8-carboxylic acid as a colorless product, mp 120 to 122 · ⁰ C (sintering 117 ° C)

f ~ O (~ n ⁵ = -118 ° (c = 1%, ethanol).

Example 2

/ ~~ 7 (S) -8S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / 4,4 / nonane-8-carboxylic acid

Argon is passed through a cold solution of 8.5 ml of concentrated ammonia in 20 ml of water. Then, 4.0 g (0.013 mol) / ~7 (S), 8S_7-7 - / "3- (acetylthio) -2-methyl-1-oxopropyl __ / -1,4-dioxo-7-azaspiro / 4.4 The mixture is stirred for a few minutes in an ice bath and then for 2 hours under argon at room temperature

ml of ethyl acetate, cooled, stirred and with 30

Acidified 16 ml hydrochloric acid (1: 1). The phases are separated. The aqueous phase is extracted twice with a further 30 ml of ethyl acetate. The Essigsäureäthylesterextrakte are combined and dried over MgSO ,,. Evaporation of the solvent gives / 7 (S), 8S / - "

7- (3-Mercapto-2-methyl-1-oxo-propyl) -1,3-dioxo-azaspiro-4,7-nonan-8-carboxylic acid as a solid residue. The "pro-

- 28 - 21 806 1

The product is ground under diethyl ether. The evaporation process is repeated. The product is then treated with 30 ml of hexane, cooled for 1 hour, filtered under argon and dried under reduced pressure. This gives 2.7 g / "7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1, ^ - dioxo-T-azaspiroj ^ 4.4_ / nonane-8-carboxylic acid as colorless solid from mp 131 to 133 ° C (sintering 125 ° C) r ~ oc_7p ⁵ = -66 ° (c = 1%, ethanol).

Example 3

(S) -1- / 3- (acetylthio) -2-methyl-1-oxopropyl 7-4,4-dimethoxy-L-proline

a) N-carbobenzyloxy-4,4-dimethoxy-L-proline methyl ester

A solution of 7.8 g (0.03 mol) of N-carbobenzyloxy-4-keto-15

L-proline of Example 1 in 60 ml of methanol is treated with 96 ml of trimethyl orthoformate and then with 0.6 ml of concentrated sulfuric acid and allowed to stand overnight at room temperature.

The pale yellow solution is treated under stirring with 1.5 g of potassium carbonate and then with 30 ml of water. The majority of the solvent is removed by means of a rotary evaporator. The resulting syrupy residue is shaken out with 30 ml of water and 30 ml of chloroform. After separating the phases, the aqueous phase is extracted 3 times with 30 ml of additional chloroform. The combined organic phases are washed with 45 ml of saturated sodium chloride solution and dried over MgSO. ₁ dried. After evaporation of the solvent to obtain 8.4 g (88 percent of th.) N-Carbobenzyloxy-4,4-dimethoxy-L-proline methyl ester. ,

b) N-carbobenzyloxy-4,4-dimethoxy-L-proline

8.4 g (0.026 mol) of the ester of (a) are dissolved in 80 ml of methanol, added dropwise at -1 to 4 ° C with 18 ml (0.036

^Γ - »- 21806 1 ^Ί

* Mol) 2 η sodium hydroxide solution and then left for 1 hour at 0 ⁰ C and overnight at room temperature. Efewith half of the solvent is removed with a rotary evaporator. The remaining solution is diluted with 150 ml of water, washed with 100 ml of diethyl ether (the washing is verwor'fen), acidified under cooling with 63, ml hydrochloric acid (1: 1) to pH 2 and Ά times with 750 ml Extracted ethyl acetate. The combined extracts are washed with 50 ml of saturated sodium chloride solution and dried over MgSO ^ _1. After evaporation of the solvent gives 8.0 g of a pale yellow, viscous Gla. This oil is dissolved in 35 ml of ethanol, treated with 3> 0 g of cyclohexylamine in 10 ml of ethanol and diluted with ml of diethyl ether. After seeding and trituration, crystalline N-carbobenzyloxy-4,4-dimethoxy-L-proline cyclohexylamine salt precipitates. After cooling overnight, 7.0 g of product are obtained, mp 157-159 ° C (sintering 151 ° C).

-? fi η ·. -

£ οίΛ · = -34 (c = 1%, ethanol). This material is recrystallized from 100 ml of acetonitrile. The salt is obtained in the form of a colorless solid of mp. 158 to 16O ° C (sintering 154 ⁰ C). ,

/ rf7 " ⁶ = -33 ° (c = 1%, ethanol).

The N-carbobenzyloxy-4,1'-dimethoxy-L-proline cyclohexylamine salt is suspended in 40 ml of ethyl acetate, stirred and treated with 25 ml of 1N hydrochloric acid. After the appearance of two clear phases, the phases are separated. The aqueous phase is extracted 3 times with 40 ml of additional ethyl acetate. The combined organic phases are dissolved over MgSO ₂ . dried. The solvent is evaporated to a final pressure of 0.2 torr at 40 °. This gives 7.2 g (70 percent of th.) Of N-carbobenzyloxy-4,4-dimethoxy-L-proline as a pale yellow viscous syrup

 35

c) 4,4-dimethoxy-L-proline

218 0 6 1

A solution of 72 g (0.022 mol) of N-carbobenzyloxy-4,4-dimethoxy-L-proline in 210 ml of methanol / water (2: 1) is treated with 2.3 g of 5% palladium-on-carbon for 6 hours shaken in a Parr hydrogenator. The catalyst is filtered off under nitrogen and washed with methanol. The combined filtrates are evaporated, the final pressure being 0.1 to 0.2 Torr.

A partially crystalline residue is obtained. This 10th

The residue is taken up in 200 ml of methanol. The evaporation process is repeated. When the solid is rubbed under diethyl ether (the evaporation process is repeated), 3.6 g (95 percent of th.) Of 4,4-dimethoxy-L are obtained.

proline as almost colorless solid of mp. 192 to 194 ° C 15

(Dec.)

= - ⁴ ? ⁰ ( ^c = '1%, methanol).

After recrystallization of a sample of methanol / diethyl ether ej

(Dec.)

Ether gives a colorless product of mp 197-198 ° C.

/ C (Jp = -49 ° (c = 1%, methanol).

d) (S) -1- / ~~ 3- / acetylthio) -2-methyl-1-oxopropyl 7-4,4-dimethoxy-L-proline

A solution of 3.3 g (0.019 mol) of 4,4-dimethoxy-L-proline in 50 ml of water is cooled with stirring to 5 C and by adding a 25% (w / v) sodium carbonate solution to the pH Value 8.5. Subsequently, with continued stirring and cooling, a solution of 3.8 g (0.021 mol) of D-3-acetylthio-2-methylpropanoylchlorid in 5 ml of diethyl ether added in portions, the pH by adding portions of 25 percent sodium carbonate in the range of 7.5 to 8.5 is maintained. After the pH has stabilized at 8.2 to 8.4 (after about 15 minutes) is stirred for a total of 1 hour and

- ³¹ - 21 80 6 1

cooled. The solution is then washed with 50 ml of ethyl acetate (the washing liquid is discarded), covered with 50 ml of ethyl acetate, cooled, stirred, carefully acidified with hydrochloric acid (1: 1) to pH 2.0 and saturated with sodium chloride. After separation of the phases, the aqueous phase is extracted 3 times with 50 ml of additional ethyl acetate. The organic phases are combined over MgSO _1, dried. The solvent is evaporated off, the final pressure being 0.2 Torr. This gives 6.7 g of a syrupy product. This syrup is treated in 70 ml of ethyl acetate with 3.9 g of dicyclohexylamine. This gives 6.5 g of colorless (S) -1-/-3- (acetylthio) -2-methyl-1-oxopropyl-74,4-dimethoxy-L-proline dicyclohexylamine salt in 2 yields of 3.1 and 3.4 - g. The F. is 158 to 16O ° C (sintering 145 ° C). r <Xj ^ = -71 ° (c = 1%, · ethanol).

After recrystallization from 20 ml of hot ethyl acetate / 60 ml of hexane, 6.0 g of colorless salt of mp 158-166 ⁰ C (sintering 155 ° C)

Ί ~ * Ί ^ - -69 ° (c = 1%, ethanol).

The dicyclohexylamine salt is converted to the free acid by dissolving 5.0 g of the salt in 50 ml of ethyl acetate.

ester suspended. The suspension is cooled and treated with 60 ml of 10% potassium bisulfate solution. 2 clear phases are obtained. After separating the phases, the aqueous phase is extracted 3 times with 50 ml of ethyl acetate. The combined organic phases are over

MgSOu dried. The solvent is evaporated to a final pressure of 0.1 to 0.2 Torr, at 45. This gives 4.1 g (69 percent of th.) Of (S) -1-/-3- (acetylthio) -2-methyl-1-oxopropyl-7-4,4-dimethoxy-L-proline in the form of a viscous, almost glassy material

³⁵ V ^- OC _- T ^ ⁵ = -112 ° (c = 1%, ethanol).

L '. -; JT -

Γ. , .

- 32- 218061

Example 4

(S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline

Argon is passed through a cold solution of 8.5 ml of concentrated ammonia in 20 ml of water for 1/4 hour. This solution is added under cooling and under argon to 4.1 g (0.013 mol) of (S) -1- / -3- (acetylthio) -2-methyl-1-oxopropyl-7-4,4-dimethoxy-L-proline. The mixture is stirred in an ice-bath, giving a pale-tan solution after about 15 minutes. The mixture is then stirred under argon at room temperature for a further 2 hours. Then the solution is extracted with 30 ml of ethyl acetate. This operation and also the following measures are carried out as far as possible under argon. The aqueous phase is stirred, cooled, layered with 30 ml of ethyl acetate and treated portionwise with about 16 ml of hydrochloric acid. (1: 1) acidified. After separating the phases, the aqueous phase is extracted 3 times with 30 ml of additional ethyl acetate. The combined Essigsäureäthylesterphasen are dried over MgSO. After evaporation of the solvent, 3.5 g (100 percent of th.) Of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline as a colorless, viscous syrup.

£ & ^ 3? = ~ ⁷² ° ^(c = ¹ ° / °, ethanol).

3.4 g of the latter product are treated with 20 ml of ethyl acetate, ground, diluted with 3Ö ml of hexane and cooled. This gives 2.6 g of a colorless solid from F. 108 to 110 ° C.

/ ~ CV_7p ⁵ = -77 ° (c = 1%,. Ethanol).

B e i-s ρ i e 1 5

(S) -1- / ~ 3- (Acetylthio) -2-methyl-1-oxopropyl) -4,4-diethoxy-L-proline

t) N-carbobenzyloxy-4,4-diethoxy-L-proline ethyl ester

λ!) in Λ ¹ · j? & '

- 33 - 2 1 80 6 ί

According to example 3 (a), using ortho

ethyl trisäthylester instead of ortho-ants, <Isäiaretrimethylester and using ethanol instead of methanol, 10.8 g of N-carbobenzyloxy-4,4-diethoxy-L-proline ethyl obtained in the form of a yellow oil ^

b) Jf-carbobenzyloxy-4,4-diethoxy-L-proline

10.8 g (0.03 mol) of the crude ester of part (a) are saponified according to 'Example 4 (b) with 70 ml of sodium hydroxide solution. After addition of 30 ml of ethanol in 10 ml portions, a solution is obtained giving 10.5 g of a yellow viscous oil. This oil is dissolved in 100 ml of diethyl ether and treated with 3.0 g of cyclohexylamine. After Animp-, fen and trituration is obtained 8.3 g of crystalline N-carbobenzyloxy-4 ^ -diäthoxy-L-proline cyclohexylamine salt, mp 123 to 126 ° C (sintering 114 ⁰ C).

Ä7d ^{6 =} " ³² ° ^{(C = 1%, Äthano1} ) · '

This material is recrystallized from 20 ml of acetonitrile. This gives 7.0 g of colorless salt, mp 125-128 ° C (sintering 115 ⁰ C).

l ~ kl ^ - -31 ° (c = 1%, ethanol).

The N-carbobenzyloxy-4, il-diethoxy-L-proline cyclohexylamine salt is suspended in 40 ml of ethyl acetate, stirred and treated with 20 ml of 1 N hydrochloric acid. After separating the phases, the aqueous phase is extracted 3 times with 40 ml of 'additional ethyl acetate. The or-

₀ ganic phases are combined and dried over MgSO 4. After evaporation of the solvent, 5.6 g (56 percent of th.) Of N-carbobenzyloxy-4,4-diethoxy-L-proline as a light yellow oil.

c) 4,4-diethoxy-L-proline

A solution of 5.6 g (0.017 mol) of N-carbobenzyloxy-4,4-di-

218061

Ethoxy-L-proline in 180 ml of ethanol / water (2: 1) is treated with 2 g of 5 percent palladium-on-carbon and shaken for 6 hours at a hydrogen pressure of 3 at. The crude, partially solid product is first rubbed under ethanol and then under diethyl ether, wherein the evaporation process is repeated in each case. To give 3 g (91 percent of theory) of 4,4-diethoxy-L-proline as a nearly colorless solid, melting at 172 to 174 ⁰ C (dec .; before gradual darkening and sintering). Γ "βί_7ρ ⁶ = -40 ° (c = 1%, methanol).

⁰ l 25 H ₂ O 52 C calc .: 52 , 03 Found .: , 22

H N 8.49 6.74

8,59 6,69 15

d) (S) -1- / 3- (acetylthio) -2-methyl-1-oxopropyl-7-4,4-diethoxy-L-proline

2.9 g (0.014 mol) of 4,4-diethoxy-L-proline of part (c) and 3 g (0.017 mol) of D-3-acetylthio-2-methylpropionyl chloride are dissolved in 3.5 ml of diethyl ether and dissolved in 35 ml Water in the presence of sodium carbonate according to Example 3 (d) implemented. 5.4 g of a pale yellow viscous oil are obtained. This oily product is treated in 40 ml of ethyl acetate with 2.6 g of dicyclohexylamine and diluted with 60 ml of hexane. In 2 yields, 4.9 g of (S) -1-tert-butyl-3-acetylthio-2-methyl-1-oxopropyl-4,4-diethoxy-L-proline dicyclohexylamine salt of melting point 13.5 are obtained to 138 ⁰ C (sintering 132 ⁰ C). After recrystallization from 15 ml of hot ethyl acetate / 45 ml of hexane, 4.2 g of crystalline colorless salt of mp. 138 to 14O ° C (sintering 135 ⁰ C). l ~ o ( 7 ^ ⁶ = -63 ° (c = 1%, ethanol);

23 ^N : C 61 , 33 9 H, 15 5 N, 30 6 S, 06 Found .: 61 48 9 , 55 5 25 5 91

^Γ -35-. 21806 1 ^Ί

The dicyclohexylamine salt is converted to the free acid by adding 4.2 g of the salt in 40 ml of acetic acid.

äthylester suspended. The suspension is cooled and treated with 40 ml of 10% potassium bisulfate solution.

2 phases are obtained. After the phases have been separated, the aqueous phase 3 is extracted with 50 ml of ethyl acetate each time. The combined organic phases are washed over MgSOj. dried. After evaporation of the solvent, 3.0 g (61 percent of theory) of (S) -1-yl-3- (acetylthio) -2-methyl-1-oxopropyl-7-4,4-diethoxy L-proline as a pale yellow, viscous syrup.

Example 6

(S) -4,4-diethoxy-1- (3-mercapto-2-methyl-1-oxopropyl) -L-proline

Argon is passed through a cold solution of 5.5 ml of concentrated ammonia in 13 ml of water for 1/4 hour. The solution is then added under cooling and under argon to 3.0 g (0.0086 mol) of (S) -1- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl_7-4,4-diethoxy-L- given proline. The mixture is worked up according to Example 4. This gives 2.4 g (92 percent of theory) of (S -) - 4,4-diethoxy-1- (3-niercapto) -2-methyl-1-oxopropyl) -L-proline as a virtually colorless viscous syrup , / oc7ί: ⁶ = -64 ° (c = 1%, ethanol).

C 1 3H ₂₃ NO ₅ , 0 25 H ₂ O C 38 7 H 4 N 10 S calc .: 50, 68 7 , 64 4 , 52 10 35 Found .: 50, 96 , 78 , 07

Example?

/ "" 2 (S), 3S 7-2- / ~ 3-acetylthio) -2-methyl-1-oxopropyl 7-6,10-dioxo-2-azaspiro / 4.5 / decane-3-carboxylic acid a) N- carbobenzyloxy-4,4-trimethylenedioxy-L-proline

By reacting 8.2 g (0.031 mol) of N-carbobenzyloxy-4-gg keto-L-proline and 45 ml (0.62 mol) of 1,3-propanediol in 450 ml of benzene in the presence of 500 mg of p-toluenesulfonic acid

L. -T

21806 1

12.3 g of a crude viscous ester. This product is saponified with 70 ml of 1N sodium hydroxide solution. 10.6 g of N-carbobenzyloxy-4,4-trimethylenedioxy-L-proline are obtained in the form of a yellow oil. This oil is dissolved in 40 ml of ethanol / 400 ml of diethyl ether and treated with 3.2 g of cyclohexylamine. This gives 10.1 g of N-carbobenzyloxy-4, 4-trimethylenedioxy-L-proline cyclohexylamine salt, mp. 163-165 ° C (sintering 16O ° C).

/ öc_7p = -27 ° Cc = 1%; Ethanol). After crystallisation of 9.8 g of this salt from 300 ml of acetonitrile, 9.5 g of colorless cyclohexylamine salt of melting point 165 ° -167 ° C. (sintering 162 ^° C.) are obtained.

Λ "ο (_7ρ ⁵ = -27 ° '(ο- = 1%; ethanol.

9.0 g of the cyclohexylamine salt are suspended in 40 ml of ethyl acetate. The suspension is stirred, cooled and treated with 45 ml of T η hydrochloric acid. After separating the phases, the aqueous phase is extracted 3 times with 40 ml of additional ethyl acetate. The organisehen phases are combined over MgSO. ₁ dried. After evaporation of the solvent gives 7.1 g (75 percent of theory) of N-carbobenzyloxy-4,4-trimethylenedioxy-L-proline in the form of a glassy product.

b) 4,4-trimethylenedioxy-L-proline

A solution of 7.1 g (0.022 mol) of N-carbobenzyloxy-4,4-trimethylenedioxy-L-proline in 200 ml of methanol / water (2: 1) is hydrogenated in the presence of 2 g of 5% palladium on carbon. This gives 3.8 g (93 percent of theory) of 4,4-trimethylenedioxy-L-proline in the form of a virtually fumeless solid, mp 234-236 ° C. (decay, before gradual darkening and sintering)

£ ~ ot_Jv ⁵ - -36 ° (c = 0, "5%, methanol / water = 1: 1).

C ₈ H ₁₃ NO ₄ CH; N

Calc .: 51.33 7.00 7.48 Found: 51.42 7.11 7.40

^Γ .- 37 - .21 80 6.1- ^Ί

^ / ~ 2 (S), 3S 7-2- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl-6-6,10-dioxo-2-azaspiro / 4,5 / decane-3-carboxylic acid

, '-'. '.is «S ι

3.7 g (0.02 mol) of 4,4-trimethylenedioxy-L-proline are treated with 4.0 g (0.022 mol) of D-3-acetylthio-2-methylpropionyl chloride in 50 ml of water in the presence of sodium carbonate according to Example , 1 (§) acylated. This gives 7.3 g of a glassy crude product.

This product is mixed with 3.6 g dicyclohexylamine in 70 ml 10

Essigsäureäthylester converted into the dicyclohexylamine salt. After inoculating and rubbing the crystalline salt precipitates. This gives 7.5 g of dicyclohexylamine salt of F. up to 170 ⁰ C (sintering 166 ° C).

/ ~ oc 7 ^ ⁶ = -59 ° (c = 1%, ethanol) ~~ ~~ ^υ

After recrystallization from 30 ml of acetonitrile, 6.5 g of colorless salt of mp 169-171 ° C. / "o (7 ° = - 63 ° (c = 1%, ethanol).

- - U

The dicyclohexylamine salt is converted to the free acid by suspending 6.4 g of the salt in 75 ml of ethyl acetate and treating with stirring 75 ml of 10% potassium bisulfate solution until 2 phases are formed. After separating the phases, the aqueous phase becomes

Extracted 4 times with 75 ml of ethyl acetate. The or-Zo

ganic phases are combined and dried over MgS (X. After evaporation of the solvent, 4.3 g (67 percent of the th.) are obtained. ~~ 2 {S) , 3S_7-2-½-3-ethylcetylthio) -2- methyl-1-oxopropyl _ / - 6,10-dioxo-2-azaspiro _ / _ 4,5 __ / decane-3

carboxylic acid in the form of a glassy product. 30

Examples

/ "" 2 (S), 3S 7-2- (3-mercapto-2-methyl-1-oxopropyl) -6,10-dioxo-2-azaspiro / 4,5 / decane-3-carboxylic acid

4.3 g (0.013 mol% of S-2, 3S-7-2-yt "3-acetylthio) -2-methyl-1-oxopropyl-6-10,10-dioxo-2-azaspiro_ / ~ 4,5_ / decan-3-carboxylic

L _r -

'λ. λ a λ SA

-38- 218061

acid are hydrolyzed 8.5 ml of concentrated ammonia in 20 ml of water according to Example 2. This gives 0.9 g of a colorless solid

/ "T *. T ?: ⁵ = -64 ° (c = 0.5%, ethanol).

Another 0.8 g of product is obtained by extraction of the aqueous phase with chloroform.

7_ ~~ <x_7 _D = -66 °. The two yields are dissolved in chloroform, evaporated and triturated under diethyl ether. After further evaporation, 1.7 g (46 percent of th.) _ / F "2 (S), 3S_7-2- (3-mercapto-2-methyl-1-oxopropyl) -6,10 ~ dioxo-2 -azaspiro_ / ¥, 57decan-3-carboxylic acid, melting at 169 to 171 ⁰ C. (sintering 167 ° C). ·

jTcx_7p ⁶ = -71 ° (c = 1%, methanol).

C ₁₂ H ₁₉ NO ₅ SC HN S

Cons .: 49.81 6.62 4.84 11.08 Found: 49.67 6.67 4.93 11.10

Beispiel'9

/ ~ 7 (S), 8S 7-7- / ~ 3- (ethylacetylthio) -2-methyl-1-oxopropyl 7-7-

: - '- ZT ^ -ζ -

aza-1,4-dithiaspiro / 4,4 / nonane-8-carboxylic acid

a) N-carbobenzyloxy-4,4-ethylenedithio-L-proline methyl ester

A solution of 3.9 g (0.014 mol) of N-carbobenzyloxy-4-keto-L-proline methyl ester in 60 ml of methylene chloride is treated under stirring with 3 ml (0.036 mol) of ethanedithiol, cooled to 8 ° and under argon treated with 3 ml (0.024 mol) of boron trifluoride etherate. After removal of the cooling bath, the pale yellow solution is stirred for an additional 1 hour and then left at room temperature overnight. Then the solution is stirred, treated with several pieces of crushed ice and then with 20 ml of water. After minutes, the phases are separated. The aqueous phase (50 ml) is extracted 3 times with 30 ml of additional methylene chloride. The combined organic phases are washed with 50 ml of saturated sodium chloride solution and dried over MgSO _1, dried. After evaporation of the solvent

Γ "· ·

218 0 6 1

with a rotary evaporator, 6 g (100 percent of th.) of N-carbobenzyloxy-4,4-ethylenedithio-L-proline methj ^ Leste'r in the form of a pale yellow oil.

b) N-carbobenzyloxy-4,4-ethylenedithio-L-proline

|, 4 g (about 0,0,18 mol) of the Methylesters of part (a) * advertising derv ¹ dissolved in 65 ml ^ methanol. The solution is treated dropwise at -1 to 4 ° C with 14.5 ml (0.029 mol) of 2N sodium hydroxide solution and then at 0 C and over 10 for 1 hour

Leave at room temperature overnight. Then it will

, remove about half of the solvent with a rotary evaporator. The remaining solution is diluted with 125 ml of water, washed with diethyl ether (the washing liquid is discarded), acidified to pH 2 with 5 ml hydrochloric acid (1: 1) with cooling and 4 times with 50 ml each time Extracted ethyl acetate. The combined extracts are washed with 50 ml of saturated sodium chloride solution and dried over MgS (X. After evaporation of the solvent, 6 g of a pale yellow viscous oil are obtained.) This oil is dissolved in 25 ml of ethanol with 1.8 g of cyclohexylamine in 5 ml of ethanol The reaction mixture is diluted with 300 ml of diethyl ether, and the crystalline cyclohexylamine salt precipitates upon seeding and rubbing in. After cooling overnight, 5.7 g of N-carbobenzyloxy-4,4-ethylenedithioxide are obtained.

L-proline cyclohexylamine salt, m.p. 205-207 (sintering

201 °). After recrystallization from 50 ml of ethanol / 400 ml of diethyl ether, 4.9 g of colorless salt of mp 207 to 209 ⁰ C (sintering 201 ⁰ C)

ο _Λ / ~ <* "/" η ⁵ = - ¹ 5 ° (c = 1%, chloroform).

4.8 g of the Cyclohexylaminsalzes are suspended in 25 ml of ethyl acetate, stirred and treated with 25 ml of 1 η hydrochloric acid. After formation of 2 clear phases, the phases are separated. The aqueous phase is extracted 3 times with 25 ml of additional ethyl acetate. The Ver-

... "" - 218061

agreed organic layers over MgSO. ₁ dried. After evaporation of the solvent, 3.8 g (62 percent of th.) Of N-carbobenzyloxy-UjU-ethylenedithio-L-proline are obtained as a pale yellow viscous syrup.

c) 4, U-A'thylendithio-L-proline hydrobromide

3.7 g (0.011 mol) of N-carbobenzyloxy ^^ - ethylenedithio-L-proline are treated with 20 ml of hydrogen bromide in acetic acid (30 to 32 percent), loosely closed and stirred with a magnetic stirrer. The mixing proves to be difficult due to the viscosity of the starting material. The starting material is broken up as far as possible with a spatula. At the same time a crystalline product begins to separate. Additional amounts of hydrogen bromide ·

in acetic acid are added after 15 minutes (10 ml) and after 25 minutes (5 ml). The mixture is then stirred until a total time of 35 minutes. By adding 250 ml of diethyl ether, the precipitation of the product is completed. After 15 minutes of cooling, the cream-colored material is filtered off under nitrogen, treated with diethyl ether.

and wash under reduced pressure and / dried. This gives 2.7 g of 4, 4-Ä'thylendithio-L-proline hydrobromide, mp 240-242 ° C (dec .; sintering and darkening from about 200 ⁰ C). ·

O oc_Tq ⁶ - -40 ° (c = 0.5%, chloroform / methanol = 1: 1).

d) / ~ 7 (S), 8S 7-7- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl 7-7-aza-1,4-dithiaspiro / 4,4 / nonane-8-carboxylic acid

A solution of 2.6 g (0.0091 mol) of 4,4-ethylenedithio-L-proline hydrobromide in 25 ml of water is cooled to 5 ° C and added by addition of a 25% sodium carbonate solution (w / v) brought the pH 8.2. With continued stirring and cooling, a solution of 1.9 g (0.01 mol) of D-3-acetylthio-2-methylpropionyl chloride in 2.5 ml of diethyl ether is added portionwise, the pH being reduced by dropwise addition of 25% sodium carbonate solution

- ¹¹¹ - 218061

V is maintained in the range of 7.5 to 8.2. After stabilization of the pH in the range of 8.2 to 8.5 (after about 15 χ minutes) is further stirred and cooled (1 hour in total).

Then the solution is washed with 25 ml of ethyl acetate (the washing liquid is discarded), covered with 25 ml of ethyl acetate, cooled, stirred, vorsichtfg with hydrochloric acid (1: 1) acidified to pH 2.0 and saturated with sodium chloride. After separating the phases, the aqueous phase is added 3 times with 25 ml each.

extracted additional ethyl acetate. The combined organic phases are dried over MgSCL. The solvent is evaporated, with the pressure on; Final 0.2 Torr. This gives 2.6 g of a syrupy product which begins to crystallize. This product is treated in 30 ΐηΓ ethyl acetate with 1.5 g of dicyclohexylamine. This gives 3.0 g of colorless dicyclohexylamine salt, mp. 176-178 ° C (sintering 170 ⁰ C).

 / ~ cx_7p = -55 ° (c = 1%, ethanol). This product is triturated in a mortar with 15 ml of acetonitrile, 1 hour.

cooled, filtered and washed with 5 ml of cold acetonitrile and with diethyl ether. This gives 2.9 g Dicyclohexylaminsalz F. 177-179 ° C (sintering 172 ° C). Γα 7J: ⁶ = -56 ° (c = 1%, ethanol).

C ₁₃ H ₁₉ NO ₄ S. C ₁₂ H ₂₃ NCHNS

Calculated: 56.56 7.98 5.28 18.12 F: 56.21 8.18 5.05 18.00

The aforementioned dicyclohexylamine salt is converted to the free acid 30

transferred by suspending 2.8 g of salt in 30 ml of ethyl acetate. The suspension is cooled and treated with 30 ml of 10% potassium bisulfate solution. 2 clear phases are obtained. After separating the phases, the aqueous phase is extracted 3 times with 30 ml of ethyl acetate each time.

'trades. The combined organic phases are over

^Γ . «-. 21 80 61

MgSO. ₁ dried. The solvent is evaporated, at the end of a pressure of 0.1 to 0.2 Torr at 45 ° prevails.

This gives 2.0 g (63 percent of th.) / J (S), 8S_7-7W ~ 3- (acetylthio) -2-methyl-1-oxopropyl_7-7-aza-1, ^ -αΙΐηίβΒρίΓοΤΤΓ. ^^ δ Nonane-8-carboxylic acid as a colorless solid from mp 125 to

126 ° C (sintering 122 °). /

/ "of T ^ ⁶ = -101 ° (c = 1%, ethanol).

Step Example. 110th

/ "" 7 (S), 8s 7-7- (3-Mercapto-2-methyl-1-oxopropyl) -7-aza-1,4-dithiaspiro ["4.4. 7nonane-8-carboxylic acid

Argon is passed through a cold solution of 3.5 ml of concentrated ammonia in 8.5 ml of water for 15 minutes. The solution is quenched under cooling and under argon to give 1.9 g (0.0054 mol) of i ~ 7 (S) , 8S_7-7- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl_7- Added 7-aza-1,4-dithiaspiro_A 4.4_ / nonane-8-carboxylic acid. The mixture is stirred in an ice bath until a solution is formed. The mixture is then stirred for a further 2 hours under argon at room temperature. Subsequently, the solution is extracted with 15 ml of ethyl acetate under argon. The aqueous phase is cooled, stirred, covered with 15 ml of ethyl acetate and acidified in portions with about 6.5 ml of hydrochloric acid (1: 1). The phases are separated. The aqueous phase is extracted 3 times with 15 ml of additional ethyl acetate. The combined Essigsäureäthylesterphasen be dried over MgSO ₁ ^. After evaporation of the solvent, a glassy residue is obtained, which solidifies on trituration under diethyl ester. The evaporation

_on operation is repeated. The resulting colorless product becomes 30

suspended in 30 ml of hexane, filtered and dried under reduced pressure. This gives 1.4 g (84 percent of theory) / ~ 7 (S), 8S_7-7- (3-mercapto-2 _: methyl-1-oxopropyl) -7-aza-1,4-dithiaspiro ^ 4.4_ / nonane-8-carboxylic acid of mp 116 to - _K 118 ° C (sintering 105 ° C). -

ToU £ = -M (c = 1%, ethanol).

Γ .. _ Λ 4 «3» A / 4

- 43 - 21

be .: 42 97 5 , 57 4 , 56 31 , 29 100% gef. : 42 70 5 , 71 4 , 54 31 16 100%

'Example 11

, 8S T-7- (3-Mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspirol / 4.5 / decane-8-carboxylic acid

a) / ~ 7 (S), 8S 7-7- / ~ 3- (acebylthio) -2-methyl-1-oxopropyl 7-1,4-dioxo-7-azaspiro / ~ 4 .5 / decane-8- carboxylic acid

According to Example T, using an equivalent amount of N-carbobenzyloxy-5-keto-L-pipecolic acid in place of N-carbobenzyloxy-4-keto-L-proline in part (c) and then following the procedure of part (d) and (e) / ~ 7 (S), 8S_7-7-jf "3- (acetylthio) -2-methyl-1-oxopropyl_7-1,4-dioxo-7-azaspiro _ / _ 4.5_ / decane-8-carboxylic acid ,

b) / ~7 (S), 8S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / 4.5 / decane-8-carboxylic acid

The product of part (a) is hydrolyzed according to example 2 with concentrated ammonia. Obtained J_ 7 (S), 8S _ / - 7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro l_ 4 .5 __ / decane-8-carboxylic acid.

Example 12

, 2S 7-1- (3-mercapto-2-methyl-1-oxopropyl) -5,5-dimethoxy-2-piperidine-carboxylic acid a) / ~ 1 (S), 2S 7-ί- / ~ 3- (acetylthio) 2-methyl-1-oxo-propyl 7- 5 _> 5-dimethoxy-2-p'-piperidinecarboxylic acid

Following the procedure of Example 3, using N-carbobenzyloxy-S-keto-L-pipecolic acid instead of N-carbobenzyloxy-4-keto-L-proline in part (a) / "1 (S), 2S_7 -1 -_ / _ ~ 3- (acetylthio) -2-methyl-1-oxopropyl_7-5,5

dimethoxy-2-piperidinecarboxylic acid

 35

^r I ,,, '- 21 80 6 1

b) / "" 1 (S), 2S 7-1- (3-mercapto-2-methyl-1-oxopropyl) -5,5-dimethoxy-2-piperidinecarboxylic acid ,

The product of part (a) is hydrolyzed according to example 4 with concentrated ammonia. One obtains / ~~ 1 (S), 2S 7-1-. "" ""

(3-Mercapto-2-methyl-i-oxopropyl) -5,5-dimethoxy-2-piperidine carboxylic acid.

Example 13

/ ~~ 1 (S) , 2-7-1- (3-mercapto-2-methyl- 1-oxopropyl) -4 , 4-

^c - * - ^c " ² .

dimethoxy-2-piperidinecarboxylic acid

a) / ~ 1 (S), 2 ^ 7-1- / 3- (acetylthio) -2-methyl-1-oxopropyl 7-4,4-dimethoxy-2-piperadinecarboxylic acid

According to Example 3, using an equivalent amount of N-carbobenzyloxy-4-keto-2-pipecolic acid instead of N-carbobenzyloxy-4-keto-L-proline in part (a) Γ Λ (S), 2ί_7-1 - / ~ 3- {acetylthio) -2-methyl-1-oxopropyl_7-4, 4-dimethoxy-2-piperidinecarboxylic acid.

b) / "" KS), 2-7-1- / 3-mercapto-2-methyl-1-oxopropyl-4,4-dimethoxy-2-piperidinecarboxylic acid

The product of part (a) is hydrolyzed according to example 4 with concentrated ammonia. This gives ] _1 (S) ", 2- (1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-2-piperidinecarboxylic acid.

 , In-game 14

£ 3S 7-2- (3-Mercapto-2-methyl-1-oxopropyl) -6,10-dithia-2-azaspiro / 4- 4.5 / decane-3-carboxylic acid

a) / ~ 2 (S), 3S 7-2- / 3 ^ acetylthio) -2-methyl-1-oxopropyl) -6,10-dithia-2-azaspiro / ~ 4.5 dodecane-3-carboxylic acid

According to Example 9, using 1,3-propanedithiol instead of, from fithandithiol in part (a) / "2 (S), 3S_7 2-_ / ~ 3- (acetylthio) -2-methyl-1-oxopropyl_7-6 , 10-dithi-2-azaspiro_ / ~ 4,5_7decane-3-carboxylic acid.

^Γ -45- 21 8 0 6.1

b) / ~ 2 (S), 3S 7-2- (3-mercapto-2-methyl-1-oxopropyl) -6,10-dithia-2-azaspiro / 4.5 / decane-3-carboxylic acid

The product of part (a) is hydrolyzed according to the method of example 10 with concentrated ammonia. This gives _T "2 (S), 3S_7-2- (3-mercapto-2-methyl-1-oxopropyl) -6,10-dithia-2-azaspiro / 4.5_ / decane-3-carboxylic acid.

B e i s ρ i e 1 15

/ ~ * 7 (S), 8S7-7- (3-mercapto-2-methyl-1-oxopropyl) -1-oxo-4-thia-7-azaspiro / 4,4 / nonane-8-carboxylic acid

a) / ~ 7 (S), 8S 7-7- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl 7-1-oxo-4-thia-7-azaspiro / 4,4 / nonane-8-carboxylic acid

According to Example 1 is obtained using 2-mercapto

ethanol in place of ethylene glycol in part (c) / ~ 7 (S), 8s7-ίo ^^ -

1-J_ 3- (Acetylthio) -2-methyl-1-oxopropyl_ / - 1-oxo-4-thia-7-azaspiro _ / _ 4.4_7nonane-8-carboxylic acid.

b) / ~7 (S), 8S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -1-oxo-4-thia-7-azaspiro / 4.4 / nonane-8-carboxylic acid

The product of part (a) is hydrolyzed according to example 2 with concentrated ammonia. Obtained _ / J ~ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1-oxo-4-thia-7-azaspiro j_ 4.4_ / nonane-8-carboxylic acid ,

Example 16

(8s) -7- / 3- (acetylthio) -2-trifluoromethyl-1-oxo-propyl-7-1,4-dioxo-7-azaspiro / 4,4-nonano-8-carboxylic acid (isomers A and B) . '

a) D, L-3- (acetylthio) -2-trifluoromethylpropionic acid

10 g (0.071 mol) of (X-trifluoromethylacrylic acid (prepared according to J. Chem. Sqc, 1954, p. 371) are cooled in a salt / ice / water bath and treated portionwise with 5.7 ml (0.075 mol) of 97 Percent treated thiolacetic acid.

After the addition, the yellow liquid is in the 1 hour

L. J ~

- * ⁶ - 218061

Cold stirred. Subsequently, the mixture is allowed to warm to room temperature. The distillation gives 14 g (91 percent of theory) of D, L-3- (acetylthio) -2-trifluoromethylpropionic acid as a light yellow oil of bp 149-153 ° C / 13 Torr. The material solidifies when stored in the cold.

b) D _> L-3- (acetylthio) -2-trifluoromethylpropionyl chloride

7 g (0.032 mol) of D, L-3- (acetylthio) -2-trifluoromethylpropionic acid are mixed with 18 ml (0.25 mol) of redistilled thionyl chloride. The mixture is refluxed for 3 hours. The residue obtained after removal of the excess thionyl chloride with a rotary evaporator is distilled. This gives 6.8 g of D, L-3- (acetylthio) -2-trifluoromethylpropionyl chloride as a pale yellow oil. from bp 80 to 82 ° C / 16 Torr.

c) (8S) -7- / 3- (acetylthio) -2-trifluoromethyl-1-oxopropyl 7-1, 11-dioxo-T-azaspiro / 4.4 / nonane-8-carboxylic acid

(Isomers A and B)

2.4 g (0.014 mol) of 4,4-ethylenedioxy-L-proline are treated with 3.4 g (0.014 mol) of D, L-3- (acetylthio) -2-trifluoromethylpropionyl chloride in 40 ml of water in the presence of sodium carbonate according to Example 1 (e) implemented. This gives 4.5 g of a nearly colorless solid, mp. 126 to 145 ° C (sintering 115 ° C)

/ ~ k T ^ ⁵ = -34 ° (c = 1%, ethanol).

4.2 g of the diastereoisomer mixture are suspended in 45 ml of diethyl ether, stirred for 2 hours and cooled for 20 minutes. The undissolved solid is filtered off, washed with cold diethyl ether and dried in air. This gives 2.7 g of product of mp 166-172 ° C (sintering 14O ° C) Yjxjft ⁵ = -62 ° (cr 1%, ethanol).

This material is then ground in a mortar with 25 ml of diethyl ether, filtered after 15 minutes, with a little

- * 7 - 2 18061

Washed diethyl ether and dried again in air. 2.1 g of product are obtained, mp. 172-177 ° C (sintering 143 ° C). After crystallization from 11 ml of boiling isopropanol and after cooling overnight, there are obtained 1.55 g of (8S) -7-π-3- (acetylthio) -2-trifluoromethyl-1-oxopropyl-7-1,4-dioxo-7-azaspiro ^ 4.4_ / nonane-8-carboxylic acid (isomeric A) as a colorless solid, mp 192-194 ° C (sintering 183 ° C). jfc <_7p ⁵ = -32 ° (c = 1%, ethanol)

 A sample recrystallized from isopropanol has a

F. 193-195 ⁰ C (sintering 184 ° C). rbc ^ / p ⁵ = -13 ° C (c = 1%, ethanol).

The isomer B is obtained by combining the aforementioned diethyl ether and isopropanol filtrates. After removal of the solvents under reduced pressure, 2.2 g of a pale yellow solid, mp. 108 to 109 ° C (sintering 95 ° C). · · ·

./~<*_7p ⁵ = + 30 ° (c = 1%, ethanol).

This material is obtained by crystallization from 6 ml of iso-

propanol cleaned. This gives 1.2 g of a nearly colorless solid, mp. 153-155 ° C (sintering 130 ⁰ C).

/, o (_ / _D = +40 (c = 1%; ethanol) After crystallization from 4 ml of ethyl acetate / 6 ml of hexane, 1.1 g of (8S) -7- / ~~ 3-acetylthio) -2 are obtained trifluoromethyl-1-oxopropyl-7-1,4-dioxo-7-azaspiro-4,4- / nonane-8-carboxylic acid (isomer

B) from mp 153 to 155 ° C (sintering 141 ° C).

/ ~ cK_7p ⁵ = + 41 ° (c = 1%, ethanol).

Example Ί7 30

(8S) -7- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -1,4- dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid (isomer A)

1j45 g (0.0039 mol) of the isomer A of Example 16 are hydrolyzed according to Example 2 for 1 hour with 2.5 ml of concentrated ammonia in, 6 ml of water. This gives 1.25 g (97 percent

S C 12 4 H 4 N 9 S 17 F About: 40 10 4 , 28 4 25 9 , 74 17 , 31 Found .: 40 , 43 , 51 , 63 10

^Γ . »Β- 2 1 80 6 1

d. Th.) (8S) -7- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -1, 4-dioxo-7-azaspiro _J /_4.4_7nonan-8-carboxylic acid (isomer A) as a glassy product , '/ ~ cC 7? ⁵ = -61 ° (c = 1%, ethanol).

Thin layer chromatography: R _f 0.40 (95: 5: 5 = methylene chloride: methanol ·: acetic acid; visualization SH reagent, PMA and heating). / -

The above acid is dissolved in ethyl acetate and treated with 1-adamantanamine. The 1-adamantanamine salt is obtained, mp 213-215 ° C (dec.). _ / _ ~ QWp ⁵ = -47 ° (c = 1%, methanol). ,

Example 18

(8S) -7- (2-Mercapto-2-trifluoromethyl-1-oxopropyl) -1,4-dioxo-azaspiro / 4-4 / nonane-8-carboxylic acid (isomer B)

1.05 g (0.0028 mol) of the isomer B of Example 16 are hydrolyzed according to Example 2 with 2 ml of concentrated ammonia in 5 ml of water. This gives 0.9 g (97 percent of theory) of (8S) -7- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -1,4-dioxo-7-azaspiro _ / _ 4.4_ / nonane 8-carboxylic acid (isomer B) as a pale yellow viscous syrup.

, Γο (7 ^"5 = -16 ° (c = 1%, ethanol), the material solidified to a waxy solid melting at 61 to 64 C (sintering 55 ⁰ C)..

C ₁ H ₁₁₁ F-NCVS. 0.25 HOC HN SF

1114 3 5s

Calcd.: 39.58 4.38 4.20 9.61 17.01 Fe.:39.60 4.28 4.26 9.62 16.88

-49- 2180 6-1

B ice ρ ie 1 19 1- / 3- (acetylthio) -2-trifluoromethyl-1-oxopropyl T-4, H-

: dimethoxy-L-proline

(Isomers A and B)

According to Example 16, using 4,4-di-

  methoxy-L-proline instead of 4,4-ethylenedioxy-L-proline in part (c) 1- / 3- (acetylthio) -2-trifluoromethyl-1-oxopropyl-4,4-dimethoxy-L-proline as racemic Mixture. This Geraisch can be separated according to Example 16 into the individual isomers.

B e i s ρ i e 1 20

1- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -4,4-dimethoxy- L-proline . ,

(Isomers A and B)

The individual isomers of Example 19 are hydrolyzed according to Example 4 with concentrated ammonia. The isomers A and B are obtained.

Example 21

/ 7 (S), 8S / -7- (3-mercapto-2-mercaptomethyl-1-oxopropyl) -1-dioxo-azaspiro / 4.4 / nonane-8-carboxylic acid a) / ~7 (S), 8S 7-7 / ~ 3- (acetylthio) -2- (acetylthiomethyl) -T- oxopropyl / -1, 4-dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid

According to Example 1, using D-2-acetylthiomethyl-3-acetylthiopropionyl chloride in place of D-3-acetylthio-2-methylpropionyl chloride in part (s) / 7 (S), - - ~ -

8S __ / - 7-yl _ 3- (acetylthio) -2- (acetylthiomethyl) -1-oxopropyl _ / - 1,4-dioxo-7-azaspiro _ / _ 4.4 __ / nonane-8-carboxylic acid.

b) / ~7 (S), 8S 7-7- (3-mercapto-2-mercaptomethyl-1-oxo- propyl-1,4-dioxo-7-azaspiro / ~ 4.4 7nonan-8- carboxylic acid

^ - ^ ² ^ :

The product of part (a) is hydrolyzed according to example 2 with concentrated ammonia. We obtain ] _ 7 (S), 8S _ / -

L. ,

^Γ - 50 - 21 806 1

7- (3-mercapto-2-mercaptomethyl-1-oxo-propyl) -1,4-dioxo-7-azaspiro _ / _ 4.4_ / nonane-8-carboxylic acid.

Example 22

(S) -1- (3-Mercapto-2-mercaptomethyl-1-oxopropyl) -4,4-dime thoxy-L-proline ' ^:

a) (S) -1- / 3- (acetylthio) -2- (acetylthiomethyl) -1-oxopropyl / -4,4-dimethoxy-L-proline

According to Example 3, using D-2-acetylthiomethyl-S-acetylthiopropionyl chloride instead of D-3-Acetylthio-2-methylpropionyl chloride in part (d) (S) -1- J_ 3- (acetylthio) -2- (acetylthiomethyl ) -1-oxopropyl _ / - 4,4-dimethoxy-L-proline. ··

b) (S) -I-C3-mercapto-2-mercaptomethyl-1-oxopropyl) -4,4-dimethoxy-L-proline

The product of part (a) is hydrolyzed according to example 4 with concentrated ammonia. One obtains (S) -1- (3-mer)

capto-2-mercaptomethyl-i-oxopropyl) -4,4-dimethoxy-L-proline.

Example 23

(8S) -7- (3-mercapto-2-methylthio-1-oxopropyl) -1,4-dioxo- 7-a zaspiro / 4.4 / non an -8 -carboxylic acid

--- j.

a) 3- (acetylthio) -2- (methylthio) -propionic acid ·

12.5 g (0.094 mol) of 2- (methylthio) -acrylic acid methyl ester (prepared from 2-chloroacrylic acid methyl ester according to Gundesmann et al., Chemische Berichte, Bd. 94 (1916), p.

3254) are stirred under ice-cooling with 94 ml of 1 N aqueous sodium hydroxide solution. The mixture is then allowed to warm to room temperature and stirred. 5 hours. The resulting solution is washed with diethyl ether and then acidified to pH 2 with concentrated hydrochloric acid. The solid precipitate is extracted into methylene chloride. The solution is washed with saturated sodium

-si- 21806 1

Triumchloridlösung washed. After evaporation of the solvent to give 2- (methylthio) -acrylic acid as a solid residue from mp 70 to 75 ° C, which is used immediately for the subsequent reaction.

Equimolar amounts of 2- (methylthio) -acrylic acid and thiol * acetic acid are added. Argon mixed and stirred at 80 ° C for several hours. 3- (acetylthio) -2- (methyl)

thio) propionic acid

 10

, b) 3- (acetylthio) -2- (methylthio) -propionic acid chloride

3- (Acetylthio) -2- (methylthio) propionic acid is refluxed for 2 hours in thionyl chloride. Subsequently · . The reaction mixture is distilled to remove excess thionyl chloride. The product is distilled under reduced pressure. 3- (acetylthio) -2- (methylthio) -propionic acid chloride is obtained.

c) (8S) -7- / 3- (acetylthio) -2-methylthio-1-oxopropyl 7-1,4-dioxo-7-azaspiro / 4,4 / nonane-8-carboxylic acid

4,4-Ethylenedioxy-L-proline is reacted according to Example 1 (e) with 3- (acetylthio) -2- (methylthio) -propionic acid chloride. One obtains (8S) -7- / "3- (acetylthio) -2-methylthio-1-oxopropyl-1, 4-dioxo-7-azaspiro_ / _ ~" 4.4_ / nonane-8-carboxylic acid.

d) (SS 1 -O-mercapto-methylthio-i-oxopropyl-i, 4-dioxo-7-azaspiro / 4,4-tanon-8-carboxylic acid

The product of part (c) is mixed according to example 2 with con

treated centered ammonia. This gives (8S) -7- (3-mercapto-2-methylthio-i-oxo-propyl) -1,4-dioxo-7-azaspiro

Example 24

l_ (3_Mercapto-2-methylthio-1-oxopropyl) -4,4-dimethoxy-L-proline

^r -sz- 21 80 61 ^η

a) 1- / 3- (acetylthio) -2-methylthio-1-oxopropyl 7-4, itdimethoxy-L-proline

According to Example 3 (d), 4,4-dimethoxy-L-proline is reacted with 3- (acetylthio) -2- (methylthio) -propionic acid chloride. This gives λ -] _ 3- (acetylthio) -2-methylthio-1-oxopropyl_7-4,4-dimethoxy-L-proline.

b) 1- (3-mercapto-2-methylthio-1-oxopropyl) -4,4-dimethoxy-L-proline

The product of part (a) is hydrolyzed according to example 4 with concentrated ammonia. 1- (3-mercapto-2-methylthio-1-oxopropyl) -4,4-dimethoxy-L-proline is obtained.

B ic ρ ie 1 25 (8S) -7- (3-mercapto-1-oxopropyl) -1-dioxo-T-azaspiro / 4,4 / nonane-8-carboxylic acid ·

a) (8S) -7- / 3- (acetylthio) -1-oxopropyl 7-1,4-dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid

4,4-Ethylenedioxy-L-proline is in accordance with Example 1 (e) with

Reacted S-acetylthiopropionyl chloride. One obtains (8S) -7-jT ~ 3- {acetylthio) -1-oxopropyl_7-1,4-dioxo-7-azaspiro_ / ~ * 4.4__7- .. nonane-8-carboxylic acid.

b) (8S) -7- (3-mercapto-1-oxopropyl) -1,4-dioxo-7-azaspiro

/4.4 / nonane-8-carboxylic acid -

The product of part (a) is hydrolyzed according to example 2 with concentrated ammonia. One obtains (8S) -7- (3-3Q mercapto-i-oxopropyl-1,4-dioxo-7-azaspiro _ / _ 4.4_ / nonane-8-carboxylic acid.

  B e .i pi e 1 26

1- (3-mercapto-1-oxopropyl) -4 _y 4-dimethoxy-L-proline a) 1 - / "~ 3- (acetylthio) -1-oxopropyl 7-4,4-dimethoxy-L-proline

4,4-Diethoxy-L-proline is prepared according to Example 3 (d) with L. J-

^Γ -53- 218061

3-Aeetylthiopropionylchlorid implemented. This gives 1 - / _ 3- (acetylthio) -1-oxopropyl 7-4,4-dimethoxy-L-proline.

b) 1- (3-mercapto-1-oxopropyl) -4,4-dimethoxy-L-proline

The product of part (a) is prepared according to example 4 with con

^ ^! hydrolyzed centered ammonia. 1- (3-mercapto-1-oxopropyl) -4,4-dimethoxy-L-proline is obtained.

_n B ice ρ ie 1 27

(8S) -7- (4-mercapto-1-oxobutyl) -1,4-dioxo-7-azaspiro- / 4.4 / nonane-8-carboxylic acid

a) (8S) -7- / 4- (acetylthio) -1-oxobutyl 7-1,4-dioxo-7

azaspiro / 4.4 / nonane-8-carboxylic acid . · -.

4,4-Ethylenedioxy-L-proline is reacted according to Example 1 (e) with 4-acetylthiobutyroyl chloride. This gives 8 (S) -7- ] _ 4- (acetylthio) -1-oxobutyl_ / -1,4-dioxo-7-azaspirOj / _ 4.4_7-nonane-8-carboxylic acid.

b) (8S) -7- (4-mercapto-1-oxobutyl) -1,4-dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid

The product of part (a) is hydrolyzed according to example 2 with concentrated ammonia. One obtains (8S) -7- (4-

V, "

Mercapto-1-oxobutyl) -1,4-dioxo-7-azaspiro ^ 4.4 __ / nonane-8-carboxylic acid. ,

B ic ρ ie 1 28 1- (4-mercapto-1-oxobutyl) -4,4-dimethoxy-L-proline

a) 1- / 4- (acetylthio) -1-oxobutyl 7-4,4-dimethoxy-L-proline

4,4-Dimethoxy-L-proline is reacted according to Example 3 (d) with 4-acetylthiobutyroyl chloride. 1- (4-Acetylthio) -1-oxobutyl-7-4,4-dimethoxy-L-proline is obtained.

b) T- (4-mercapto-1-oxobutyl) -4,4-dim e thoxy-L-proline

:

The product of part (a) is prepared according to example 4 with con

^Γ -5 \ - 21 80 6 1

hydrolyzed centered ammonia. 1- (4-mercapto-1-oxobutyl) -4,4-dimethoxy-L-proline is obtained.

B ic ρ ie 1 29 (8S) -7- (2-mercapto-1-oxoethyl) -1,4-dioxo-7-azaspiro · - / 4,4-tnonane-8-carboxylic acid ".

a) (8S) -7- / 2- (acetylthio) -1-oxoethyl 7-1,4-dioxo-7-azaspiro / 4,4 / nonane-8-carboxylic acid

4,4-Ethylenedioxy-L-proline is reacted as described in Example 1 (e) with acetylthioacetyl chloride to give (8S) -7- / 2- (acetylthio) -1-oxoethyl-7-1,4-dioxo-7 azäspiro7 / 4.4j7 nonane-8-ocarboxylic acid.

b) (8s) -7- (2-mercapto-1-oxoethyl) -1,4-dioxo-7-azaspiro

- ~

/ 4.4 / nonane-8-carboxylic acid

The product of part (a) is hydrolyzed according to example 2 with concentrated ammonia. One obtains - (8S) -7- (2-mercapto-1-oxoethyl) -1,4-dioxo-7-azaspiro_ / ~ "4.4_7nonan-8-carboxylic acid.

B e i s ρ i e 1 30

1- (2-mercapto-1-oxoethyl) -4,4-dimethoxy-L-proline a) 1- / 2- (acetylthio) -1-oxoethyl 7-4,4-dimethoxy-L-proline \.

4,4-Dimethoxy-L-proline is reacted according to Example 3 (d) with acetylthioacetyl chloride. This gives 1-_ / _ 2- (acetylthio) -1-oxoethyl _ / - 4,4-dimethoxy-L-proline.

b) 1- (2-mercapto-1-oxoethyl) -4,4-dimethoxy-L-proline

The product of part (a) is hydrolyzed according to example 4 with concentrated ammonia. 1- (2-Mercapto-1-oxoethyl) -4,4-dimethoxy-L-proline is obtained.

L. J -

-55 - 21 80 6 1

Example 31

(8S) -7- (3-mercapto-2,2-dimethyl-1-oxopropyl) -1, ^ -dioxo-7-azaspiro / i 4.4 / nonane-8-carboxylic acid

a) (8S) -7- / 3- (acetylbhio) -2 _> 2-dimethyl-1-oxopropyl 7-1, 12-dioxo-T-azaspiro / 4,4 / nonane-8-carboxylic acid

4,4-Ethylenedioxy-L-proline is reacted according to Example 1 Ce) with 3-acetylthio-2,2-dimethylpropionyl chloride. One obtains (8S) -7- / ~ 3- (acetylthio) -2,2-dichloro-1-oxopropyl_7-1,4-dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid.

' b) (8S) ^ - 7- (3-Mercapto-2,2-dimethyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / 4,4 / nonane-8-carboxylic acid

The product of part (a) is hydrolyzed with concentrated ammonia. There are obtained (8S) -7- (3-mercapto-2,2-dimethyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / 4,4,4-nonan-8-carboxylic acid.

Example 32 1- (3-Mercapto-2,2-dimethyl-1-oxopropyl) -4,4-dimethoxy-L-proline

a) 1- / 3- (acetylthio) -2,2-dimethyl-1-oxopropyl 7-4,4-dimethoxy-L-proline

4,4-Dimethoxy-L-proline is in accordance with Example 3 (d) with

3-acetylthio-2,2-dimethylpropionyl chloride implemented. This gives 1-ω-acetylthio-2,2-dimethyl-1-oxopropyl-7-4,4-dimethoxy-L-proline.

b) 1- (3-mercapto-2,2-dimethyl-1-oxopropyl) -4,4-dimethoxy

ι 'ι ·

L-prolm

The product of part (a) is hydrolyzed according to example 4 with concentrated ammonia. 1- (3-mercapto-2,2-dimethyl-1-oxopropyl) -4,4-dimethoxy-L-proline is obtained.

Γ Π

- ⁵⁶ - 21 80 6 1

Example 33

/ "" 7 (S) _t 8S 7-7- (3-Mercapto-2-ethyl-1-oxopropyl-7-t, 4-dioxo-7 * -azaspiro / 4.4 / nonane-8-carboxylic acid "

a) / ~ 7 (S), 8S 7-7- / ~ 3- (acetylthio) -2-ethyl-1-oxopropyl-7-1,4-dioxo-7-azaspiro / 4,4 / nonane-8-carboxylic acid

4,4-Ethylenedioxy-L-proline is reacted according to Example 1 (e) with D-3-acetylthio-2-ethylpropionyl chloride. Man'erhält ./. "7 (S), 8S_7-7- / ~ 3- (acetylthio) -2-ethyl-1 -oxopropyl_7-1,4-dioxo-7-azaspiro / ~ 4.4 7nonane-8-carboxylic acid.

b) / ~7 (S), 8S 7-7- (3-mercapto-2-ethyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid

The product of part (a) is hydrolyzed according to example 2 with concentrated ammonia. Obtained J_ 7 (S), 8S_7-7- (3-mercapto-2-ethyl-1-oxopropyl) -l, 4-dioxo-7-azaspiro / 4.4_ / nonane-8-carboxylic acid.

Example 34

(S) -1- (3-mercapto-2-ethyl · -1-oxopropyl-4,4-dimethoxy-L-proline

a) (S) -W-3- (acetylthio) -2-ethyl-1-oxopropyl 7-4,4-dithethoxy-L-proline

4,4-Dimethoxy-L-proline is reacted according to Example 3 (d) with D-3-acetylthio-2-ethyl-propionyl chloride. This gives (S) -1-ε-3- (acetylthio) -2-ethyl-1-oxopropyl-7-4,4-dimethoxy-L-proline.

b) (S) -1- (3-mercapto-2-ethyl-1-oxopropyl) -4,4-dimethoxy

L-proline 30

The product of part (a) is hydrolyzed according to example 4 with concentrated ammonia. There are obtained (S) -1- (3-mercapto-2-ethyl-1-oxoprppyl) -4,4-trimethoxy-L-proline.

L. , J -

- "- 21 80 6 1

B e i s ρ i e 1 35

/ ~ 8S 7-7- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -7 - ;, - aza-i, 4-dithiaspiro / 4.4 / nonane-8-carboxylic acid

a) 3- / ~ / ~ (4-methoxy) -phenylmethyl-7-thio-7-2-trifluoro . methylpropionyl

An undiluted mixture of 3.9 g of 1-trifluoromethylacrylic acid and 4.3 g of 4-methoxybenzylthiol is stirred at 100 to 110 C for 1 hour. Subsequently, the mixture is allowed to cool to room temperature. The solid is recrystallized from cyclohexane. This gives "i-J_ J_ (4-methoxy) phenylmethyl_7-thio_7-2-trifluoromethylpropionylic acid of mp. 72 to 74 ° C.

By treatment of this acid with thionyl chloride is obtained

- - -_ -

3, ~ X L (4-methoxy) phenylmethyl_ / - thio_ / - 2-trifluoromethyl-propionyl chloride.

b) / 8S III 3- / / (4-methoxy) phenylmethyl Athio / 2-trifluoromethyl-1-oxopropyl / 4.4 / nonane-8-carboxylic acid

_ · Trifluoromethyl-1-oxopropyl / -7-aza-1,4-dithiaspiro

The 3-J_ l_ (4-methoxy) -phenylmethyl _ / - thio _ / - 2-trifluoromethyl-propionyl chloride of part (a) is reacted according to Example 9 (d) with 4,4-fithylenedithio-L-proline. This gives _ / ~ 8S_7-7W ~ 3- / 7Z ~ (4-methoxy) phenylmethyl_7-thio_7-2-trifluoromethyl-1-oxopropyl_7-7-aza-1,4-dithiaspiro / 4_47-nonane-8 carboxylic acid.

^c ) ~ / ~ 8S 7-7-. _r (3

ρ ropyl) -7-aza-1, 4-dithiaspiro / ~ 4 .4 / nonane-8-carboxylic acid

The product of part (b) is mixed under nitrogen with trifluoroacetic acid and anisole. After removal of the solvents under reduced pressure gives as residue / ~ 8S 7-7- (3-mercapto-2-trifluoromethyl-1-oxo- _ _ _i

propyl) -7-aza-1,4-dithiaspiro _ / _ 4.4 __ / nonane-8-carboxylic acid.

- 58 - 2 1 BQ & 1

Example 36

/ "" * 8S 7-7- (3-mercapto-2-methylthio-1-oxopropyl) -7-aza-1,4-dithiaspiro / 4,4 / nonane-8-carboxylic acid

a) 3- / ~ / ~ (4-methoxy) phenylmethyl T-thio 7-2-methylthio ** propionyl chloride

3- / ~ / ~ (4-Methoxy) -phenylmethyl__7-thio_7-2-methylthiopropanoic acid, prepared according to Example 10 of US Pat. No. 4,116,962, is treated with thionyl chloride. The result is 3- / ~ / ~ ~ (4-methoxy) -phenylmethyl-7-thio-7-2-methyl- ~~

thiopropionylchlorid.

b) / "" 8S 7-7- / ~ 3- / ~ / ~ (4-methoxy) -phenylmethyl-7-thio-7-2-methylthio-1-oxopropyl / -7-aza-1,4-dithiaspiro / ~ 4 .4 7- · nonane-8-carboxylic acid

: - · -. ,

3 -_ / l_ (4-methoxy) -phenylmethyl_7-thio _ / - 2-methylthiopropionylchlorid of part (a) of Example 9 (d) is reacted with 4,4-Äthylendithio-L-proline. Obtained 8S_7-7-7 l_ ~ ~ 7V ^ 3- (4-methoxy) -phenylmethyl_7-thio_7-2-methylthio-1-oxopropyl _ / - 7-aza-1,4-dithiaspiro _ / _ 4.4_ / nonane-8 carboxylic acid.

c) / "" 8S / -7- (3-Mercapto-2-methylthio-1-oxopropyl) -7-aza-1,4-dithiaspiro / 4.4 / nonane-8-carboxylic acid The product of part (b) is added Nitrogen mixed with trifluoroacetic acid and anisole. After removal of the solvents under reduced pressure, the residue obtained is 1-8S - / - 7- (3-mercapto-2-methylthio-1-oxo-propyl) -7-aza-1,4-dithiaspiro / 4.4 / nonane-8- carboxylic acid. - -

Example 37

/ ~7 (S), 8S 7-7- (3-mercapto-3-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid

a) / ~ 7 (S), 8S 7-7- / ~ 3- ( acetylthio) -3-methyl-1-oxopropyl 7-

1,4-dioxo-7-azaspiro / 4.4 / nonane ^ -8-carboxylic acid

- 59 - dL ι 'Q ν ö »

4,4-Ethylenedioxy-L-proline is reacted according to Example 1 (e) with D-S-acetylthio-S-methylpropionyl chloride. Obtain 7 ~ 7 (S), 8S_7-7-jf 3- {acetylthio) -3-methyl-1-oxopropyl_7-1,4-dioxo-7-azaspiro _ / _ 4.4_ / nonane-8-carboxylic acid.

b) / ~ 7 (S), 8S 7-7- (3-mercapto-3-methyl-1-oxopropyl) -1,4- * ioxo-7-azaspiro / 4,4 / nonane-8-carboxylic acid The product of part (a) is hydrolyzed according to Example 2 with concentrated ammonia. This gives ] 7 (S), 8S_7-7- (3-mercapto-3-niethyl-1-oxopropyl) -1,4-dioxo-7-azaspiro- / 4,4,4-nonanoic-8-carboxylic acid.

B e i s ρ i e 1 38

(S) -1- (3-mercapto-3-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline

a) (S) -1- / 3- (acetylthio) -3-methyl-1-oxopropyl-7-4,4-dimethoxy-L-proline

4,4-Dimethoxy-L-proline is reacted according to Example 3 (d) with D-S-acetylthio-S-methylpropionyl chloride. There are obtained (S) -W.sub.3- {acetylthio) -3-methyl-1-oxopropyl_7-4,4-dimethoxy-L-proline.

b) (S) -1- (3-Mercapto-3-methyl-1-oxopropyl) -4,4-d-imethoxy-L-proline

The product of part (a) is hydrolyzed according to example 4 with concentrated ammonia. There are obtained (S) -1- (3-mercapto-3-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline. ;

B ic ρ ie 1 39 1- (3-mercapto-i-oxopropyl) -4,4-dimethylthio-L-proline a) 4-keto-L-proline hydrobromide

4.0 g (0.015 mol) of N-carbobenzyloxy-4-keto-L-proline are treated with 20 ml of hydrogen bromide in acetic acid (30 to 32 Pro-35

cent). The mixture becomes within 8 minutes

2180 6 1

often stirred up. Afterwards (the foaming is finished), the yellow-orange solution is covered with 25 ml of diethyl ether. The rubbery product is triturated. Diethyl ether is discarded. The resulting sticky solid is triturated with fresh diethyl ether and finally with 50 ml of acetonitrile. This gives 2.7 g (85 percent of theory)%-keto-L-proline hydrobromide _r as a crystalline solid, mp 153-155 ° C (dec.).

L & J ^ - - ⁴ 9 ° (c = ¹ ° / °; water)

 10

b) 1- / 3- (acetylthio-1-oxopropyl-4-oxo-L-proline

A solution of 4.1 g (0.0195 mol) of 4-keto-L-proline hydrobromide in 50 ml of water is cooled with stirring to 5 ° C and by portionwise addition of solid sodium carbonate '

carbonate (the foaming is kept under control by the addition of a few drops of diethyl ether) to a pH of 8.0, which requires about 2 g., then, with continued stirring and cooling, a solution of 3.times.5 g (0.012 mol ) 3-Acetylthiopropanoylchlorid in 5 ml of ethyl acetate in portions with a pipette, wherein the pH by dropwise addition of a 25 percent (w / v) sodium carbonate solution (about 10 ml) in the range of 7.0 to 8.0 maintained becomes. After about 10 minutes, the pH stabilizes in the range of 8.0 to 8.4. After further stirring and cooling for a total of 1 hour, the solution is washed twice with 50 ml of ethyl acetate, covered with 50 ml of ethyl acetate, stirred, cooled, cautious

with concentrated hydrochloric acid to the pH 2.0 ange-30

acidified and saturated with sodium chloride. After separation of the phases, the aqueous phase is extracted 3 times with 50 ml of additional ethyl acetate. The combined organic phases are dried over MgSO 4. The solvent is evaporated off to give a final pressure of 0.2 Torr. This gives 4.8 g of a yellow

218 0 : 6 1

orange glassy residue. This residue is dissolved in 35 ml _s of ethyl acetate and treated with a solution of 3.5 g of dicyclohexylamine in 5 ml of ethyl acetate. After inoculation and trituration, precipitates crystal-clear λ ~ 1_ 3- (acetylthio-1-oxopropyl) _ / - 4-oxo-L-proline dicyclohexylamine salt. After standing overnight, 2.7 g of a nearly colorless product are obtained, mp 191-193 ° C (decomp.).

/ I * 7 ^ ⁶ = -24 ° (c = 1%, CHClO.

This dicyclohexylamine salt is converted into the free acid according to Example 1 (e) using potassium hydrogen sulfate. This gives 3.7 g of 1-_ / ~ 3- (acetylthio) -1-oxopropyl _ / - 4-oxo-L-proline as a pale yellow glassy solid. ,

c) 1- / 3- (acetylthio) -1-oxopropyl TH, 4-dimethylthio-L - proline

1-Z 3- (acetylthio) -1-oxopropyl_M-oxo-L-proline is reacted according to Example 9 (a) with methylthiol. There is obtained 1-/-3-acetylthio-1-oxopropyl-4,4-dimethylthio-L-proline.

d) 1- (3-Mercapto-1-oxopropyl) -4,4-dimethylthio-L-proline

"The product of part (a) is hydrolyzed with concentrated ammonia as in example 2. This gives 1- (3-mercapto-1-oxopropyl) -4,4-dimethylthio-L-proline.

Example 40 / "" 2 (S), 3S 7-2- (3-mercapto-2-methyl-1-oxopropyl) -8,8-

dimethyl 6,10-dioxo-2-azaspiro / 4.5 / decane-3-carboxylic acid a) / 2 (S), 3S 7-2- / 3-acetylthio) -2-methyl-1-oxopropyl 7- ' 8,8-dimethyl-6,10-dioxo-2-azaspiro / 4.5 / decane-3

carboxylic acid 35

21806 1

According to Example 1, using 2,2-dimethyl-1,3-propanediol in place of ethylene glycol in part (c) / ~ 2 (S), 3S 7-2- / ~ 3- {acetylthio) -2-methyl 1-oxopropyl 7-8,8-dimethyl-6,10-dioxo-2-azaspiro_ / ~ 4.5_7decan-3-carboxylic acid.

b) / ~ 2 (S), 3S 7-2- (3-mercapto-2-methyl-1-oxopropyl) -8,8 -dimethyl-6, 10-dioxo-2-azaspiro / 4.5 / decane-3 carboxylic acid .

The product of part (a) is hydrolyzed according to example 2 with concentrated ammonia. This gives J_ 2 (S), 3S_7-2- (3-mercapto-2-methyl-1-oxopropyl) -8,8-dimethyl-6,10-dioxo-2-azaspiro _- / ~ 4,5_7decan-8 _- carboxylic acid ,

Example 41

"" 7 (S), 8S 7-7- (3-Mycap! To 2-methyl-1-oxopropyl) -1, 4-dioxo-7-azaspiro / 4,4 / nonane-2-methyl-8- carboxylic acid a) N-carbobenzyloxy-4,4- (1-methylethylenedioxy) -L-proline methyl ester

A mixture of 8 g (0.025 mol) of N-carbobenzyloxy-4,4-dimethoxy-L-proline methyl ester of Example 3 (a), 2.4 g (0.032 mol) of 1,2-propanediol, 0.4 g of p Toluenesulfonic acid monohydrate and 400 ml of toluene is heated to the reflux temperature (110 to 112 ° C). The reflux rate is adjusted so that the solvent is slowly distilled into a graduated cylinder by means of a Dean-Stark tube. After 80 ml of solvent are collected, the same volume of fresh solvent is added via a dropping funnel into the reaction flask. During a total reflux time of 1 1/4 hours, this process (removal and replacement of 80 ml of solvent) is repeated 4 times.

Subsequently, the mixture is allowed to stand overnight and then washed twice with 100 ml per liter of water. The United

21806 1

Washing liquids are extracted with 100 ml of toluene. The combined organic phases are washed over MgSOj. dried. The solvent is removed with a rotary evaporator, the final pressure being 0.2 Torr. This gives 8.2 g (99 percent of theory) of N-carbobenzyloxy-4,4- (1-methylethylenedioxy) -L-proline methyl ester as a yellow viscous oil.

b) N-carbobenzyloxy-4,4- (1-methylethylenedioxy) -L-proline

8.2 g (0.025 mol) of the crude methyl ester of part (a) are dissolved in 80 ml of methanol. The solution is added dropwise at -1 to 4 C with 18 ml (0.036 mol) of 2 η sodium hydroxide solution. Subsequently, the mixture is 1 hour

at 0 C and then at room temperature overnight

to let. After removing about half of the solvent with a rotary evaporator, the solution is diluted with 150 ml of water, washed with 100 ml of diethyl ether (the washing liquid is discarded), while cooling with 6.3 ml of hydrochloric acid (1: 1) to pH 2 acidified and extracted 4 times with 75 ml of ethyl acetate. The combined extracts are washed with 50 ml of saturated sodium chloride solution and dried over MgSO _1, dried. Evaporation of the solvent gives 8 g of a red-orange

_o viscous oil. This oil is dissolved in 50 ml of acetonitrile. The solution is heated with stirring and treated with 3.8 g of 1-adamantanamine. The corresponding salt precipitates quickly. After cooling overnight, the material is filtered off, washed with cold acetonitrile and with diethyl ether and

_"N dried under reduced pressure. This gives 10.3 g of crude Adamantanaminsalz from F. 202 to 204 ⁰ C (Zers.). / ö <7 ^ ⁶ = -13 ° (c = 1%, methanol).

After trituration with 50 ml of boiling acetonitrile and subsequent cooling to obtain 9.4 g of a pale yellow-brown salt of F. 202 to 204 ° C (dec.). / ~ oC T ^ ⁶ = - 13 ° (c = 1%, methanol).

2180 6 1

The above adamantanamine salt is suspended in 40 ml of ethyl acetate. The suspension is treated under stirring with 1 η hydrochloric acid. After formation of 2 clear phases they are separated. The aqueous phase is extracted 3 times with 40 ml of additional ethyl acetate. The combined organic layers over MgSO _1, dried. The solvent is evaporated off, the final pressure being 0.2 Torr at 40 °. This gives 5.8 g (72 percent of theory) of N-carbobenzyloxy-4,4- (1-methylethylenedioxy) -L-proline in the form of a yellow-orange viscous syrup.

c) 4,4- (1-methylethylenedioxy) -L-proline .

A solution of 5.6 g (0.017 mol) of N-carbobenzyloxy-4,4-15

(1-Methyläthylendioxy) -L-proline in 150 ml of methanol / water

(2: 1) is treated with 1.6 g of 5% palladium on carbon and shaken for 5 hours under a hydrogen pressure of 3 at. The catalyst is filtered off under nitrogen and washed with methanol. The united FiI-20

are evaporated, the pressure at the end is 0.1 to 0.2 Torr. The resulting crystalline residue is suspended in 200 ml of methanol. The residue obtained after repeating the evaporation process is added to the

Etched ethyl ether. Then it is evaporated again. 25

This gives 3.0 g (94 percent of theory) of 4,4- (1-methylethylenedioxy) -L-proline as a pale tan solid of mp 219 to. 221 ° C (Zers, before gradual darkening and sintering)

_{_rt} / ~ U 7 ^ ⁵ = -22 ° (c = 1%, ethanol / water 1: 1).

*

d) / ~7 (S), 8S 7-7- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl 7-

1,4-dioxo-7-azaspiro / ~ 4.4 7nonan-2-methyl-8-carboxylic acid

2.8 g (0.015 mol) of 4,4- (1-methylethylenedioxy) -L-proline are prepared according to Example 1 (e) with 3.0 g (0.017 mol) of D-3-acetyl-

m - f

21806

thio-2-methylpropionyl chloride in 40 ml of water. 5.0 g of a viscous yellow product are obtained. This is treated with 2.8 g of dicyclohexylamine in 45 ml of ethyl acetate. This gives 4.2 g of .gamma./7 (S), 8S_7-7-_ / -3- (acetylthio) -2-methyl-1-oxo-propyl_7-1,4-dioxo-7-azaspiro. / nonane-2-methyl-8-carboxylic acid dicyclohexylamine salt in the form of an almost colorless solid of melting point 170 ° to 172 ° C. (sintering 168 ° C.)

/ "Ι * 7 ^ ⁵ = -58 ° (c = 1%, ethanol).

After crystallization from 12 ml of acetonitrile, 3.85 g (51 percent of theory) of colorless salt, mp 170 to 172 ° C (sintering .168 ⁰ C)

/ - (X_7p ⁵ = -57 ° (c = 1%, ethanol).

^C 14 ^H 21 ^NO 6 ^S * ^C 12 ^H 23 ^{N c HN s}

: Ber.. 60.90 8.65 5.46 6.26

Filled: 60.93 8.72 5.43 6.35

The dicyclohexylamine salt is converted into the free acid by suspending 3.8 g of the salt in ethyl acetate and treating the suspension while stirring with 45 ml of 10% potassium bisulfate solution. The resulting 2 phases are separated. The aqueous phase is extracted 4 times with 40 ml of ethyl acetate. The orga-

nical phases are combined and dried over MgSO4.

After evaporation of the solvent gives 2.5 g (51 percent of theory) _T "7 (S), 8S_7-7 -_ / ~ 3- (acetylthio) -2-methyl-1-oxopropyl_7-1,4 -dioxo-7-azaspiro / ~ 4.4_7nonane-2-methyl-8-carboxylic acid as a colorless solid of mp 65 to 68 C (sintering 48 ° C).

⁵ - -100 ° (c = 1%, ethanol).

e) / ~7 (S), 8S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-

dioxo-7-azaspiro / 4,4 / nonane-2-methyl-8-carboxylic acid 35

The product of part (d) is prepared according to example 2 with con

218061

hydrolyzed centered ammonia. 2.05 g of I T (S "), 8S I - / - 7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro I4U / nonane-2 are obtained. methyl-8-carboxylic acid as a viscous colorless oil.

5 , -.- τ

/ -25 D

= -57 '

(c = 1%, ethanol).

Examples ^ to 75

According to Example 41, the dimethoxy compounds (or their alkyl esters) listed in column I are treated with the diol or dithiol indicated in column II. The spiro intermediates listed in column III are obtained. After removal of the N-protecting group (and the alkyl ester group) and acylation with the acyl chloride indicated in column IV, the product of column V is obtained, which can then be hydrolyzed to the product of column VI.

Column I

HC CH. - ³ O 0 -

ι Ι

Cbz-N

C-COOH

Column III

10

Cbz-N

C-COOH

, 4

Column II

^X l X ₂ IV H H 0 H C-Cl column

-67- 21 80 6 1

Column V

- OR "R, O ^x 27'p

π ι ⁴ ! ³ H. II

_R - _{C. S.} (CH) CCN ---. C-COOH

8 m,

I H

15 τ »

Column VI

20 ^R 9 Λθ

^x i \ /

25 ^ C.

R. R. 0 - * 2Τ'ρ 7 "2'q

, 1 ⁴ I ³ II

HS- (CH) -C-CNC-COOH

^m ι I

R ^H 30 ^R 6

- 68 -

218061

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in

in

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C **

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(N

I   cn s δ-§ e e S3 X δ- I " U - 1 • Ο - cn Ι • W E CJ-O I S I e ο - (N O - -O ο - tn CM e (N C e e

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2 1806 1

JN Ο

_JN _- UW

ü - wCN

CN

C - w

CJ -O

CN

-G

CN

CN

X X O - O

CN

5-S

X Ü - OCN

CJ

CJ

<n

CN

X X O -

O -

CN

CN

CN

CN

in

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VO

03 VO

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δ -δ υ

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In the example 41, the disubstituted compounds of column I (or their alkyl esters) are treated with one molar equivalent of the alcohol or thiol of column II. The compound of column III is obtained. Another possibility is to treat the dimethoxy-substituted compound of column I (or its alkyl esters) with a molar excess of the alcohol or thiol of column II to obtain the disubstituted compound of column IV. After removal of the N-protecting group (and the alkyl ester group) from the intermediate of column III 'or IV and after subsequent acylation with the acid chloride of column V gives the products of column VI or VII. These compounds can then be hydrolyzed to the products of column VIII or IX.

Column I Column II.

C.

(H ₂ C) _p (CH ₂ ) _q

I '

N C-COOH

I H

- ^ΊΊ - 2 t 8 O 6 1

Column III Column IV

^Λιt P P

I ¹ I ² ? 2 f ₂

A / ² ^ / 2

^(H 2f ^J P ^^^ ^(H 2 ^C) P · \ kA

IIII ² '

 N C

H H

10 Cbz-N C-COOH Cbz-N C-COOH

Column V

0 R. R- 0

15 Il I ⁴ I ³ Il

R ₀ -CS- (CH) -C-C-Cl ο ία ι

R _R .Column ^(H 2 VI C fj \ I ⁴ j 3 R (CH ₂ ) (CH) -C - Rl 5l I I - C-COOH rg H 0 0 • ^c) p H Il I R ₈ -CS- -C- M

- 78 - 21

Column VII

O R. R,

Il I ⁴ I ³ Il

R ₈ -CS- (CH) _1n -CC

C-COOH ι

Column VIII

R ₁ R ₂

Γ

RP Π / Η PI

I ⁴ I ³ H ² I

HS- (CH) -C-C N

πι C-COOH

21806 1

Column IX

HS- (CH)

R O

II

C- C

I ^Λ C-COOH

25

30

Oh, I

- 80 -

21

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15

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20

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35

Φ • Η Cl W

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21806 1

cn

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in

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20

CS

cn

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ΓΟΟ

35

2180 6 1

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¹ 5

Β " (Q) S

CJ

«Η γΗ

U   χ X 8 " ro δ ro CJ ^ -CH. S ro CJ

PO

Q CCI ρο # U approx HO ro CJ OH PO CN δ HO HO = CJ CJ CN U (N -O- (N S Il CN CM X X X ^ HO-O- X jj " C X X -O-C ο-ο- CJ O jn -O-C -O-C -O-C 0-0- 0-0- -O-C tn in X ro "Vm υ ro X ro S U c / ¹ δ -O- δ M a r j CJ O -O- -Ο -0- -0- ό ό

35

ο r-4 cn σ " cn in VO r- co ω ω ω cn cn cn cn

CJ

XO

.0

co

X CJ

co

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co

ΓΜ

CJ

co

Vi I

CJ

cn ι

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ro

CJ

in

CJ O

CJ X O U I I ? O I

Φ

cn o

ο-

η O

2180

cn

CM

10

X t

15

O I

χ U

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20

Il S U

<Μ

CM

25

υ ο

O O

S δ

O O

χ U

X CJ

CO O

CTi O

- 85 -

218061

HrH

53

S CJ

U ^ -

I i

(Q ω

ι ι

b CJ

CJ

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δ δ S CJ ι ι I O ? O

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^Γ - 86 -. · 21 80

B e is pi e 1 125 (S, S, S, S -) - 7.7 ^> .- / '~ dithiobis- (2-methyl-1-oxo-3,1-propanediyl) / bis- / 1, U-dioxa-7-azaspiro / 4.4 / nonane-8-carboxylic acid

3.0 g (0.0109 mol) r "7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1, 4-dioxo-7-azaspiro _ / _ 4.4_ / nonane 8-carboxylic acid of Example 2 are dissolved in 80 ml of water, the pH of the solution is adjusted to 6.5 with 1N sodium hydroxide solution, and this solution is added dropwise with stirring to a total of 11 ml of 0.5M iodine solution 95% ethanol (6.34 g iodine / 50 ml solution), keeping the pH in the range of 5.5 to 6.5 by addition of 1N sodium hydroxide solution and after 15 minutes, traces of excess iodine by adding dilute sodium thio

eliminated sulfate solution. The solution is reduced to about 50 ml one-15

concentrated, cooled and acidified with hydrochloric acid (1: 1).

Then, 30 ml of methylene chloride are added. The mixture is saturated with sodium chloride and stirred. After separating the phases, the aqueous phase is washed 3 times with 20 each

extracted ml of additional methylene chloride. The united 20

organic phases are over MgSO ₁ . dried. The solvent is then evaporated off, the final pressure being 0.2 Torr. The brittle residue is ground under diethyl ether. After evaporation of diethyl ether to obtain 2.8 g of pale yellow solid residue. This product is redissolved in 50 ml of methylene chloride and washed 3 times with 10 ml of water. The combined aqueous phases are extracted with 20 ml of methylene chloride. The combined organic layers over MgSO. ₁ dried. After evaporation and trituration with diethyl ether to give 2, ag (73 percent of theory) (S, S, S, S) -7,7 ^f - / ~ dithiobis- (2-methyl-1-oxo-3, i -propandiyl) _7bis Γ ~ λ, 4-dioxo-7-azaspiro _ / _ 4.4_7nonan-8-carboxylic acid as a cream colored amorphous solid, melting at 61 to 63 ° C (foams; sintering \, 5O ⁰ C).

£ oi _ / ^ = -.92 ° (c = 1%, ethanol)

- - 87 - 6 2 H 1 4 80 6 1 S H ₂ O C 6 , 05 4 N , 31 About: 46 , 63 , 29 , 94 11 96 gef. : 46 , 52 , 63 10

Be as ρ ie 1Ί26 (S, S, S, S) -7,7 '- / ~ dithiobis- (2-met'hyl - oxo-3,1-propanediyl) 7-bis-Y 7-aza-1 , 4-dithiaspiro / 4.4 / nonane-8-carboxylic acid

jf ~ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -7-aza-1,4- ^ O dithiaspiro_ / ^ 4.4_ / nonane-8-carboxylic acid from Example 10 reacted according to Example 125 with iodine. (S, S, SS) -7,7 '- / - dithiobis- (2-methyl-1-oxo-3,1-propanediyl) 7-bis- [ 7-aza-1, 4-dithiaspiro] 4.4_ / nonane-8-carboxylic acid.

Example ^?

(S, S, S, S) -1,1 ^t - / - Dithiobis- (2-methyl-1-oxo-3,1-propanediyl) 7-bis- / 4,4-dimethoxy-L-proline /

(S) -1- (3-Mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline of Example 4 is reacted with iodine according to Example 125. (S, S, S, 'S) -1, 1 ^f- _ / ~ dithiobis-1-methyl-1-OXO-3,1-propanediyl) (7-bisT_) 4-dimethoxy-L-prolin_7.

Example 128

/ "" 7 (S), 8 (S) 7-7- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl-7-1,4-dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid methyl ester

A solution of the product of Example 1 in diethyl ether is treated with a slight excess of diazomethane. After 2 hours of standing at room temperature which is _ _n evaporated solvent. One obtains / ~ 7 (S), 8S 7-7- / ~~ 3- (acetylthio) -2-methyl-1-oxopropyl_7-1,4-dioxo-7-azaspiro _ / _ 4.4_ / nonane-8 carboxylic acid-methylester.

Example 129 / "" 7 (S), 8S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / 4,4 / nonane-8-carboxylic acid methyl ester

The product of Example 128 is hydrolyzed according to Example 2 with concentrated ammonia. This gives methyl 7-methyl ( J_ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro-) - (-> 4,4-nitrono-8-carboxylate.

, , , -

.Example. 130

(S) -1- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl 7-4,4-dimethoxy-L-proline methyl ester

A solution of the product of Example 3 in diethyl ether 10

is treated with a small excess of diazomethane.

After standing at room temperature, the solvent is evaporated. There are obtained (S) -1-/-3- (acetylthio) -2-methyl-1-oxopropyl-4,4-dimethoxy-L-proline methyl ester.

Example 131

(S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline methylester

The product of Example 130 is hydrolyzed according to Example 4 with concentrated ammonia. There are obtained (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline methyl ester.

B ice ρ ie 1 132 Sodium salt of / ~ 7 ('S), 8S 7-7- (3-mercapto-2-methyl-1-0X0-propyl) -1,4-dioxo-7-azaspiro / ~ 4 Λ 7nonan-8-carboxylic acid

A solution of 1.0 g of the product of Example 2 is dissolved in 10 ml of water. The solution is treated with 1 equivalent of sodium bicarbonate. After freeze-drying the solution man.das sodium salt obtained by l_ 7 (S), 8S _ / - 7- (3-mercapto-2-methyl-1 -oxopropyl) -1,4-dioxo-7-azaspiro _ / _ 4.4_7- ' nonane-8-carboxylic acid.

Similarly, using potassium

bicarbonate the corresponding potassium salt.

2130 6 1

Example 133

Sodium salt of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline

1.0 g of the product of Example 4 is dissolved in 10 ml of water. The solution is treated with 1 equivalent of sodium bicarbonate. After freeze-drying of the solution, the sodium salt of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline is obtained.

The corresponding potassium salt is obtained in similar manner using potassium bicarbonate.

Example 131. '

1000 tablets of the composition indicated below are prepared:

_ / ~ 7 (S), 8S_7-7-0-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro _ / _ 4.4_ / nonane-8-carboxylic acid 100 mg

Cornstarch 50 mg

Gelatin 7.5 mg

microcrystalline cellulose

(Avicel) 25 mg

Magnesium stearate 2.5 mg

185 mg

The active ingredient and the corn starch are mixed with an aqueous solution of gelatin. The mixture is dried and ground to a fine powder. Subsequently, the microcrystalline cellulose and the magnesium stearate are admixed with granulation. The mixture is then compressed in a tablet press to 1000 tablets with an active ingredient content of 100 mg.

 35

- 90 - 21 806 1

Example -135 According to Example 134, tablets containing 100 mg each of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline are prepared.

.. -. ''. '. "

Example 136

From the ingredients given below are 1000 tablets each containing 50 mg / L 7 (S), 8 S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro -

- -

l_ 4.4_ / nonane-8-carboxylic acid.

jT "7 (S), 8S_7-7- (3-mercapto)

2-methyl-1-oxopropyl) -1,4-

dioxo-7-azaspiro _ / _ __ 4.4 / - ^ nonan-8 _r-carboxylic acid 50 g

Lactose 100 g

microcrystalline

Cellulose (Avicel) 150 g

Cornstarch 50 g

^ Magnesium stearate 5 g

Active ingredient, lactose and microcrystalline cellulose are mixed and then mixed with the corn starch. Then the magnesium stearate is added. The dry ^ ⁵ mixture is compressed into 1000 tablets each weighing 355 mg and having an active ingredient content of 50 mg. The tablets are coated with a methylcellulose solution (Methocel E 15) containing dye containing yellow No. 6.

Example 137

According to Example 136, tablets containing 50 mg each of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline are prepared.

- 91 - 2 1 80 6

100 mg 7 mg 193 mg

Example 138

Two-part # 1 gelatin capsules are each mixed with a mixture of the following ingredients: sodium salt of V ~ 7 (S), 8S_7-

7- (3-mercapto-2-methyl-1-oxo-

propyl) -1 | 4-dioxo-7-azaspiro-

J_ 4.4_ / nonane-8-carboxylic acid

Magnesium Stearate Lactose

Example 139

According to Example 138, gelatin capsules are prepared with a content of in each case 100 mg of sodium salt of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline.

Example 140

From the ingredients given below, an injection solution is prepared:

/ _ ~ 7 (s) _> 8s_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro_ / ~ 4.4_T-nonane-8-carboxylic acid 500 g

4-hydroxybenzoic acid ·

methyl ester - 5g

4-hydroxybenzoic acid

propyl ester 1g

Sodium chloride 25 g

Water for injection

purposes. ad 5 liters

Active ingredient, preservative and sodium chloride are dissolved in 3 liters of water and then brought to a volume of 5 liters. The solution is filtered through a sterile filter and aseptically placed in pre-sterilized vials.

21806 1

brought, which are then closed with pre-sterilized rubber closures. The vials each contain 5 ml of solution for injection with an active substance concentration of 100 mg / ml.

'..',. ·. '' ·. ' · ..;. ,

B e i s ρ i e 1 141

According to Example 140, an injection solution containing (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline is prepared. 10

Example 142

6000 'tablets, each containing the following ingredients, are prepared:

V ~ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro-

l_ 4.4_ / nonane-8-carboxylic acid 100 mg

Microcrystalline cellulose

(Avicel) 100 mg

Hydrochlorothiazide 12.5 mg

Lactose (U.S.Pharmakopoe) 113 mg

Corn starch (U.S.Pharmakopoe) 17.5 mg

Stearic acid (U.S.Pharmakopoe) 7 mg

- 350 mg

The appropriate amounts of active ingredient, avicel and part of the stearic acid are mixed. The coarse ingredients are ground and passed through a # 2 sieve. Additions are hydrochlorothiazide, lactose, maize starch

and the remaining stearic acid admixed. The mixture becomes 30

pressed in a tablet press to capsule-shaped tablets, each 350 mg in weight. The tablets are provided with a groove so that they can be halved.

218061

example

According to Example 142, tablets containing (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline and hydrochlorothiazide are prepared.

Likewise, the products of Examples 1, 3 and 6 to 133 can be processed into medicaments according to the methods of Examples 134 to 143.

Claims (19)

- 9U ---- · 21806 1 Erfindunqsanspruch 1· ;. Process for the preparation of ketal and thioketal derivatives of mercaptoacylprolines of general ⁵ my formula I fi. fa R ₄ R ₃ O R ₅ -S- (CH) -C -C C ^ COOR in the R represents a hydrogen atom or a lower alkyl radical,. R ₁ and R ₂ independently of one another are lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl radicals or radicals of the general formulas or - ^tC Vn or R ₁ and R _? together form a polymethylene radical of the general formula. , mean, - 95 - 21 80 6 1 X ₁ , Xp and X- independently represent oxygen or sulfur atoms, R- and R 1 independently of one another represent hydrogen atoms, lower alkyl, lower alkylthio, - (CHp) -SH- or halogen-substituted lower alkyl radicals, Rg represents a hydrogen atom or a lower alkyl radical, with the proviso that Rg is a lower alkyl radical only if R- also denotes a lower alkyl radical, m is 0, 1 or 2, ¹⁵ η / ien is 1, 2 or 3, ρ and q each have the value 1 or 2, with the proviso that not both have the value 2, ²⁰ t has the value 2 or 3, R "e% n hydrogen atom, a C. n-alkyl, C ₁ ^ .- alkoxy, C K-alkylthio, chlorine, bromine or fluorine atom, Trifluoromethyl or hydroxyl group, 25 Rq and R _{10 are} both hydrogen atoms, both lower alkyl radicals or a radical thereof is a hydrogen atom and the other radical is a lower alkyl, halogen-substituted lower alkyl or hydroxyl-substituted lower alkyl kylrest or a radical of the general formulas (CH ₀ )
35 2 η - (CH) or 2 η 218061 mean, R c represents a hydrogen atom, a protecting group removable by hydrolysis or by chemical means, or, provided that neither R 1 nor R 1 is a radical of the general formula - (CH 2 P) -SH, a sulphide of the general formula -C- C
¹ I
R- ^(CH 2'q C-COOR means, as well as salts of these compounds, characterized in that one (1) a substituted proline or a substituted pipecolic acid of the general formula HN (CH ₂ ! COOR with an acid of the general formula . ". 218061 f ⁴ ι ³ R ·S- (CH) -G-COOH ο m ι  · - in which R ¹ , - denotes a hydrogen atom or a protective group which can be removed by hydrolysis or by chemical means, couples, or 10 (2) a compound of the general formula (H ₂ C) ₅ , (CH ₂ ) _{q | 4} | 3 υ (CH) C C N C COOR m ι * 1t; R _- R- _{| 4} | 3 R ^H 6 ' in which R ¹ , - has the abovementioned meaning, with an alcohol or thiol of the general formulas R ₁ X ₁ H, RpXpH or ο < N implements, obtaining a product in which R _{1 represents} a hydrogen atom or a protecting group removable by hydrolysis or by a chemical means, optionally protecting the protecting group to form a product in which R _{1 represents} a hydrogen atom, and optionally 2 1806 V products in which JL denotes a hydrogen atom, ¹ O general formula formation of a product in which R, - a remainder of the 2. Method according to item 1, characterized in that ρ has the value 2 and q has the value 1. 3. Method according to item 1, characterized in that ρ has the fourth 1 and q has the value 2. ^. Method according to item l, characterized in that ρ and q each have the value 1. 5. The method of item 4, characterized 'in that X ₁ and Xp are independently oxygen or sulfur atoms, R represents a hydrogen atom or a lower alkyl radical, R ₁ and R ₂ are each C. _{i.-Alkylresteoder} 2 connected methyl radicals, R ^ and R ₁ , each hydrogen or C ₁ ^ .- alkyl radicals, Rf- is a hydrogen atom, a C ₁ ^ alkanoyl or benzoyl radical and Rg is a hydrogen atom and m is 0 or 1 has. 6. The method according to item 4, characterized in that X ₁ and Xp are each oxygen atoms, R, R _1. , R ^ and Rg are each hydrogen atoms, R ₁ and R "are each C 1-4 -alkyl - 99 - 2 18061 radicals or in each case methylene groups which complete an ethylenedioxy ring and R, denotes a methyl group and m has the value 1. 7 · Method according to item 4, characterized in that X ₁ -R ₁ and X 2 ~ ^R 2 complete ^an ethylene dioxyring. 8. The method according to item 4, characterized in that R is a hydrogen atom, R ₂ , a hydrogen atom, R_ and R- are each C ₁ ^ -alkyl radicals or R, - a hydrogen atom and Rj is a hydrogen atom, a C ₁ , .-. Alkyl radical, a trifluoromethyl, methylthio or mercapto-methyl group, Rp is a hydrogen atom, a C ^ alkanoyl or benzoyl radical, X ₁ and X "oxygen or Schv / efelatome, R ₁ and Rp C ^ ii-alkyl radicals, radicals of the general formulas 'or 20 - < i! <- ^Cii 2-ir t -CH m is 0 or 1 and R "is a hydrogen, chlorine, bromine or fluorine atom or a methyl, methoxy, methylthio, trifluoromethyl or hydroxyl group. 9. Method according to item 8, characterized in that R is a hydrogen atom, -R ₂ . a hydrogen atom, R_ and R ^ both methyl groups or Rg a hydrogen atom and R_ a hydrogen atom, a methyl, trifluoromethyl, methylthio or mercaptomethyl group, Rf- a water. atom, an acetyl or benzoyl group, X ₁ and Xp - loo - 2 1 SO 6 1 have the same meaning, R, and Rp are methyl or ethyl groups or radicals of the general formulas ^R 7 "" Ff m is 0 or 1 and R _{7 is} a hydrogen, chlorine, bromine or fluorine atom or a methyl, methoxy, methylthio, trifluoromethyl or hydroxyl group. 10. The method according to item 9, characterized in that R, R ₁ , R, - and Rg are hydrogen atoms, R ~ is a methyl group, m is 1 and R, and R _{2 are} both methyl or ethyl groups. 11. The method according to item 10, characterized in that X ₁ and Xp are both oxygen atoms. 12. The method according to item 11, characterized in that 25 (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline prepared. 13 · Method according to item 11, characterized in that Man (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-di-30 ethoxy-L-proline produced. 14. The method according to item 4, characterized in that R is a hydrogen atom, R ₁ , a. Hydrogen atom, R_ and R, both C ₁ "alkyl radicals or R ^ - a hydrogen atom and 1-4 o R_ is a hydrogen atom, a C 1-4 -alkyl radical, a tri 21806 1 fluoromethyl, methylthio or mercaptomethyl, R ₁ - is a hydrogen atom, a C ₁ ^ .- alkanoyl or benzoyl, X ₁ -R ₁ and XpRp are joined to form one of the following groups. C- ^R io ' - <o \ I ^R io ^{10 H} 2 ' OS I \ / 0 p> / "^ -u or / ^ ti -V. ίΠ _ο · tr / - »/ 11 2 2 - -. « ₂ C. C. * ^! Il OO. '' R ₁₀ and R _{10 are} both hydrogen atoms or both C ₁ j, -alkyl radicals or R _{q is} a hydrogen atom and R _{10 is} a C ₁ jj-alkyl radical, hydroxyl-substituted C ₁ ^ -alkyl radical or halogen-substituted C ₁ 2, -alkyl radical and m is the value 0 or 1 has. 15. The method according to item 14, characterized in that R ₀ and R _{1n are} both hydrogen or R _{q is} a hydrogen atom and R _{10 is} a methyl, hydroxymethyl or trifluoromethyl group. - 102 - 218061 16. The method according to item 15, characterized in that R is a hydrogen atom, R ₁ . a hydrogen atom. R and Rr are both methyl groups or R, - is a hydrogen atom and R_ is a hydrogen atom, a methyl, trifluoromethyl, methylthio or mercaptomethyl group, R _{5 is} a hydrogen atom, an acetyl or benzoyl group and X ₁ -R ₁ and Xp-Rp to form one of the following radicals KC-CH, H ₉ C CH-CH., ² II ^{2 Z} \ I - ³ . H ₂ C CH ₂ , H ₂ C - CH-CH ₃ i I Il H.C CH HC CH ¹ Y I · or I \ 17. The method according to item 16, characterized by, that R, R _1. , R ₁ - and R ^ are hydrogen atoms and R-. a methyl group and m has the value 1. 18. The method according to item 17, characterized in that one prepares / 7 (S), 8S_7-7 .- (3-mercapto-2-methyl-1-oxopropyl) -1, 4-dioxo-7-azaspiro / 4,4_ / nonane-8-carboxylic acid. 19. The method according to item 17, characterized in that one jT ~ 2 (S.), 3S_7-2- (3-mercapto-2-methyl-1-oxopropyl) -6,10-dioxo-2-azaspiro _ / _ 4.5 produces / decane-3-carboxylic acid, - 103 - 218061 20. The method according to item 17, characterized in that _ / ~ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -7-aza-1, 4-dithiaspiro_ / _- 4.4 _ / nonane-8-carboxylic acid manufactures. 21. Method according to item 17, characterized in that V ~ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) - manufactures. ¹ ^ 22. The method of item 16, characterized in that R, R _11, R ₁ - R and _R are hydrogen atoms and R, a trifluoro-'m ο ο 3 methyl group and m has the value 1. Method according to item 22, characterized in that (8S) -7- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / 4,4 / nonane-8-carboxylic acid is prepared , 24. The method according to item 4, characterized in that R ^. and R ₁ . no - (CH ₀ ) -SH radical and R ₁ - a radical 3 .4 2 η 5 the general formula R ₃ Ο -S- (CH) -C C N- ra ι (L) COOR means. 25. The method according to item 24, characterized in that (S, S, S, S) -7, 7'-_ /. * ~ Dithiobis- (2-methyl-1-oxo-3,1-propanediyl) _7 to produce bis-1,4-dioxo-7-azaspiro_ / 4,4,4-nonano-8-carboxylic acid.