DE2951200A1 - KETAL AND THIOKETAL DERIVATIVES OF MERCAPTOACYLPROLINES AND PIPECOLINIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR TREATING HIGH PRESSURE - Google Patents

Description

"Ketal and thioketal derivatives of mercaptoacylprolines and -pipecolic acids, process for their preparation and their Use for treating high pressure "

The invention relates to ketal and thioketal derivatives of mercaptoacylprolines and pipecolic acids in general Formula I.

R.-S- (CH) -C -C 5 _{β |}

RR O (HC) _n

ι ⁴ ι ³ H ² I ^p

• Cj-COOR H

(I)

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

- < ^CH 2.'n

- (CH ₂ )

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] or R ₁ and R ₂ together represent a polymethylene radical of the general formula

^R 9

5 means / \

X ₁ , X ₂ and X ^ independently of one another are oxygen or sulfur atoms,

R ^ and R ₁ . independently of one another hydrogen atoms, lower alkyl, lower alkylthio, - (CH ₂ ) _n -SH- or halogen-substituted lower alkyl radicals,

R / - means a hydrogen atom or a lower alkyl radical, with the proviso that R, - only then means a lower Is an alkyl radical when R ^ is also a lower alkyl radical means,

20 m has the value O ₁ 1 or 2, η has the value 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 "ej.n hydrogen atom, a C ^^ - alkyl, C ^ -alkoxy, Cj ^ -Alkylthlorest, a chlorine, bromine or fluorine atom, a Means trifluoromethyl or hydroxyl group,

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

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or

- ^(CH 2 ⁾ n- <O ^X ' R.

mean,

) R ,. a hydrogen atom, a protective group which can be removed by hydrolysis or chemically, or, provided that neither R-. nor R ₁ ^ represent a radical of the general formula - (CHp) -3H, a sulfide of the general formula

X. X ₀

^(H 2 ^C) p

I ⁴ I ³ H

-S- (CH) -C- C

m,

means,

and salts of these compounds.

C-COOR I *

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If R ₁ and R_ together form a polymethylene chain with 3 or 4 carbon atoms, the corresponding cyclic ketals and thioketals can be represented by the following general formulas.

Preferably there is only 1 carbon atom in the polymethylene chain substituted.

Within the meaning of R.sup.1, the radicals each having one carbon atom, ie the methyl, methoxy or methylthio group, are particularly preferred _{as C 1} -C -alkyl, C ₁ -C -alkoxy and C _{1 -C -alkylthio radicals.}

The stars contained in the formulas given above indicate an asymmetrical center in the ring.

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Γ "1

In the case of proline, i.e. when ρ and q each have the value 1, this center is in the L configuration. In the case of pipecolic acid, i.e. when ρ and q, respectively have the value 2, this center is in the D, L-

5 or L configuration.

Asymmetric centers can, depending on the meaning of R ,, R |. and Rg also present in the mercaptoacyl side chains be. Another asymmetrical center can also be found in the

1.0 ring is present when X ₁ -R ₁ and Xp-Rp are different. Accordingly, the products can exist in stereoisomeric forms or as racemic mixtures. All of these forms are within the scope of the invention. In the synthesis explained in more detail below, the racemate or one of the two enantiomers can be used as starting materials. If a racemic starting material is used, the stereoisomers obtained as the end product can be separated in the customary manner by chromatographic processes or by fractional crystallization. If there is an asymmetric center in the mercaptoacyl side chain, it is preferably in the D configuration.

The mercaptoacyl derivatives according to the invention

of proline and pipecolic acid of the general formula I and the salts of these compounds are valuable active ingredients with antihypertensive effect, which can be processed into corresponding drugs.

The invention also relates to processes for the production of certain new intermediate products, which are used as starting products serve to prepare the compounds of general formula I.

³ ^ The term "lower alkyl", which is used to define the radicals R, R-, R ₂ , R_, R ₁ , and Rg means

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^Γ - 20 -

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

The term "cycloalkyl" refers to saturated rings having 3 to 7 carbon atoms, where the cyclohexyl

group is particularly preferred. 15th

The term "halogen-substituted lower alkyl" refers to the lower alkyl groups discussed above, where 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 groups.

The term "hydroxyl-substituted lower alkyl"

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

The term "lower alkenyl radical" in the context of the radicals R ₁ and Rp means monounsaturated, straight-chain or branched hydrocarbon radicals having 2 to 7 carbon atoms, such as the ethenyl, propenyl, isopropenyl and

Butenyl group. Under the term "lower alkynyl radical" 35

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

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Γ I

to understand, for example the propargyl group. Lower alkenyl radicals with 2 to 5 carbon atoms are preferred and lower alkynyl radicals having 2 to 4 carbon atoms.

Under the term "protective group removable by hydrolysis" as part of the definition of Rj-, groups are too understand that can be removed by conventional hydrolysis or ammonolysis. Acyl- ^ remnants of the general formula

Il

R ₈ -C-,

where Ro can have one of the following meanings:

Lower alkyl radical with 1 to 7 carbon atoms through or more chlorine, bromine or fluorine atoms substituted lower alkyl radical, - (CHp) -cycloalkyl radical, aryl radical, for example the general formula

^R 7

and heterocyclic radical, for example radicals of the formulas

- ^(CH 2 ^}

or *

■ -§1

^X 3 "N

where r has the value 0, 1, 2 or 3 and R "and X-, the have the meaning given above. Lower alkanoyl radicals with up to 4 carbon atoms are preferred, in particular the acetyl group, as well as the benzoyl group.

Under the term "chemically removable protective groups" within the definition of R are groups like

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Γ I

the p-methoxybenzyl,. p-methoxybenzyl

To understand oxycarbonyl, trityl and tert-butoxycarbonyl groups. These groups may be after completion of the acylation reaction to various V / else depending on the meaning of X ₁ and Ri ~ ^x p ^ 2 are ^removed, for example, trifluoroacetate by treatment with trifluoroacetic acid and anisole, sodium and liquid ammonia or mercury (II).

Preferred compounds of the general formula I are the L-proline derivatives, i.e. ρ and q both have the value 1 and R means a hydrogen atom.

With regard to the mercaptoacyl side chain, the end products preferred are those compounds in which Rp. Denotes a hydrogen atom, m has the value 0 or 1, R ₁ denotes a hydrogen atom and R and R, each are lower alkyl radicals with 1 to 4 carbon atoms, in particular both a methyl group, or in which R / - is a hydrogen atom and R ^ is a hydrogen atom, a lower alkyl radical with 1 to 4 carbon atoms, in particular the methyl group, a trifluoromethyl, Methylthio ™ or mercaptomethyl group Preference is also given to intermediate products and end products in which the side

chain R, - a lower alkanoyl radical with 1 to 4 carbon atoms, in particular the acetyl group, or a benzoyl group.

Particularly preferred end products are compounds of the general

common formula I with a mercaptoacyl side chain, in

R ₁ - denotes a hydrogen atom, m has the value 1, R ₁ , and R / - denotes hydrogen atoms, R ~ denotes a methyl group and the asymmetric carbon atom to which the

Rest Rj is bound, is in the D configuration. 35 *

With regard to the substituents on the proline ring, preference is given to those compounds in which R ₁ and R ₂ independently of one another

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nander lower alkyl radicals with 1 to 4 carbon atoms, in particular the methyl or ethyl group, or a radical of the general formulas

or

and R_ is a hydrogen atom, a methyl, methoxy or methylthio group, a chlorine, bromine or fluorine atom, a trifluorinethyl or hydroxyl group, or XiRi ^and X ₂ - ^R _{2 are} ^Rin S of ^the formulas

R ₀

I S

Ί.0

ii

C - C,

I I

O S

Ί.0

r ^R io

H-C

' ² I.

CH S

H_C

² I.

CH.

I '

or

where Rq and R _{1Q are} both hydrogen atoms or both lower alkyl radicals having 1 to 4 carbon atoms, in particular both hydrogen atoms or both methyl groups, or R- is a hydrogen atom and R _{10 is} a lower one

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The alkyl radical has 1 to 4 carbon atoms, especially the Methyl group, a hydroxyl-substituted lower alkyl radical with 1 to 4 carbon atoms, especially the Hydroxymethyl group, or a halogen-substituted lower alkyl radical, in particular the trifluoromethyl group, means.

With regard to the proline ring, those compounds are particularly preferred in which X. and X_ have the same meaning, and in particular those compounds in which XiRi ^and Xp ~ ^R 2 ^{each mean methoxy groups or ethoxy} groups in each case, or in which XjRi ^{and x} p ~ ^R 2 together form radicals of the following formulas

CH, / 3

H, C CH ₃ , HC - CH , H ₂ C CH,,

² II Il I>

OO OO S ^ S

CH

H ₂ C-CH , H ₂ C ^ CH ₂ , H ₂ C ^ CH ₂

^S ^ * S,

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

A substituted proline or a substituted Pipeco-30

Linic acid of the general formula II

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ft? 2

«Ι / 2

(H ₂ C)

HN C-COOR

I *

is with an acid or its chemical equivalent of the

general formula III

I ⁴ i ³

15 R ₅ -S- (CH) -C-COOH

in which R ¹ ^ is a hydrogen atom or a protective group which can be removed by hydrolysis or by chemical means, with the formation of a product of the general formula IV

R ₁ R,

I ¹ I ²

* 1 ^X 2

25 ^ C '

/ \ (H ₂ C) (CH)

4 f3 VI R ₅ -S- (CH) - C- CO- N C-COOR

30 'H.

^R 6

coupled.

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

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a mixed anhydride, a symmetrical anhydride, an acid halide, an active ester or among Use of Woodward reagent K, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or the like to activate. An overview of such acylation processes can be found in Houben-Weyl, Methods of Organic Chemistry, Vol. XV, Part II (1974), p. 1 ff .. The acid halide, in particular the acid chloride, is preferably the general Formula III reacted with the acid of general formula II.

If the proline or the pipecolic acid of the general formula II is reacted in the ester form, the resulting can Esters of the general formula IV, i.e. R denotes an alkyl radical, by customary processes into the free acid, i.e. R means a hydrogen atom. if R denotes, for example, an ethyl group, this ester protective 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 this salt by treatment with an aqueous one Solution of an acid, such as potassium hydrogen sulfate, converted into the free acid.

Products of the general formula IV which have an acyl radical of the general formula Rg-CO- can be obtained by conventional Hydrolysis or ammonolysis in products of general

Formula I, in which R ^ is a hydrogen atom, converted will.

The products of general formula I in which R ~

and

do not represent a radical of the general formula - (CH ₀ ) -SH and

35 ^

in which R _{5 is} a radical of the general formula

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R ₁ ΚΙ ¹ I ²

(H ₂ C) _p (CH ₂ ) _q

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

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

The esters of the general formula I, in which R denotes a lower alkyl radical, can be derived from the corresponding Carboxylic acids, i.e. R denotes a hydrogen atom, can be prepared by conventional esterification processes, for example by esterification with a diazoalkane, such as diazomethane, an i-alkyl-3-p-tolyltriazene, such as 1-n-butyl-3-p-tolyltriazene, or similar.

The disubstituted prolines or pipecolic acids of the general formula II, in which X ₁ -R ₁ and Xp-Rp have the same meaning, can be obtained by adding an N-protected keto compound of the general formula V.

Il

(H ₂ C) _p (CH ₂ ) _q (V)

ν Cr-COOR

in the Cbz means the carbobenzyloxy group, with a

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1 alcohol or thiol of the general formula VI

R ₁ -X ₁ -H (VI)

5 in the presence of an orthoformate or orthoformate the general formula

HC (X .. —R μ) -

and an acid such as concentrated sulfuric acid or

p-toluenesulfonic acid, implemented. This implementation can be done in one inert organic solvents such as benzene, acetic acid, diethyl ether or cyclohexane, preferably below Heating, for example to the reflux temperature, can be carried out; See Buehler et al., Survey of Organic Syntheses, Wiley & Sons, 1977, Vol. 1, pp. 516 to 519. The N-protected one is obtained as the product of this reaction Intermediate of the general formula VII

20 PR

> f ¹

25 (C H _{2) p} (CH _{2) q}

C-COOR

• (VII)

The N-protected intermediate of the general formula VII can with one molar equivalent of an alcohol or Thiols of the general formula VIII

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Γ Π

¹ R ₂ -X ₂ -H (VIII)

treated in accordance with the conditions set out above are obtained, the intermediate of the general formula IX being obtained.

^{l 2}

10 ^ C

(H ₂ C) _p (CH ₂ ) _q

CbZ N C-COOR

i *

When using a molar excess of alcohol or Thiols of the general formula VIII, an intermediate of the general formula X is obtained

R- R-

ι ² | 2

X ₂ x ₂

25 (C H _{2) p} (CH _{2) q}

Cbz NC _r COOR _(x)

The N-protective group can then be removed by customary processes, for example, if X. and X ₂ both represent oxygen atoms, by hydrogenation in the presence of palladium-on-activated carbon or, if one or both of the radicals X ₁ and X _{5 represent} sulfur atoms, by

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

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Γ Π

In a similar way, the spiro compounds of the general formula II, i.e. R / and R_ are in one with one another Polymethylene chain connected by reacting the keto compound of the general formula V with the alcohol or

⁵ thiol of the general formula XI

(C) _t

10 / \ (XI)

X ₁ X ₂

H 'H

in which Rq, R ₁₀ and t have the meaning given above, are obtained in the presence of an acid such as p-toluenesulfonic acid. This produces the intermediate of the general formula XII

20 ^R > 9 / * "

X ₁ X ₂

(H ₂ C

CbZ-N C-COOR (XU)

I * H

Another possibility is the disubstituted compound of the general formula VII directly with a to treat molar excess of the alcohol or thiol of the general formula XI, whereby one intermediate

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

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r ι

And RjQ means either both or neither a hydrogen atom.

As explained above, the N-protective group can then be removed, whereby the spiro compounds of the general formula II is obtained.

According to another procedure, the introduction
of the radicals X ₁ -R ₁ and X_-R _? take place in a later stage of the process. According to this embodiment, the protected keto 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

It

H N qj-COOH

H (XIII)

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

I!

_R i _s - (CH) CC (I ς, -COOH (XIV)

5 ^m I>

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1 receives.

The radicals X ₁ -R ₁ and X ₂ ~ ^R 2 ^{or the} spiro radical s * * ^c \:> vj

can · at this point according to the above Process can be introduced, whereby a product of the general formula IV is obtained.

With regard to the preparation of the starting materials and the intermediates, reference is also made to the following literature references: US Pat. Nos. 4,046,889, 4,105,776, 4,151,935 and 4,116,962; Can. J. Biochem. & Physiol., 37: 581 (1959); jaCS, 79, 189 (1957); J.Med. Chem. 21: 445 (1978); The end. J. Chem. 20: 1493-1509 (1967); Buehler et al., Survey of Organic Syntheses, Wiley & Sons, 1977, Vol. 1, pp. 516-519, Vol.

20 2, pp. 461 to 470; Chem. Pharm. Bull., Tokyo, 1978, 26: 2209 and 2217; Can. J. Chem., Vol. 47 (1969), P. 860; J.Amer .. Chem. Soc, 80, 6350 (1958); Harrison et al., Compendium of Organic Synthetic Methods, Wiley-Interscience, New York, 1971, pp. 449 bis

25 456; J. Amer. Chem. Soc, 79: 192 (1956); Bull.

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

The methods discussed here 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 can be used. Additional details can be found in the examples below, which are used as model procedures for making other members of the respective linking groups can serve.

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- ³³ - 29512Q0

* The compounds of the invention form with a number of inorganic or organic bases salts. Listed below are examples of metals and amines of which the salts can be derived from: aluminum, alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, amines such as aralkylamines, e.g. dibenzylamine and Ν, Ν-dibenzylethylenediamine, 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 can also be derived from amino acids such as arginine or lysine. The physiological Compatible salts, such as the sodium or potassium salts, can be used for the medicinal products discussed below Purposes are used and are therefore preferred. These and other salts that are not necessarily physiological must be compatible, are suitable for the isolation and purification of products suitable for the following purposes. This is illustrated in the examples for the dicyclohexylamine salt. The salts are made by the compound in the acid form with an equivalent amount of the base which provides the desired cation in one Medium in which the salt precipitates or in an aqueous medium with subsequent lyophilization. The free acid can be obtained from the salt by conventional neutralization processes, for example with potassium hydrogen sulfate or hydrochloric acid.

The compounds of the general formula I in which R ₁ . a

Hydrogen atom, a radical of the general formula

If

R ₈ -C-

or the substituent of the disulfide type, and especially the compounds in which Rj- is a hydrogen

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Γ Π

^ atom means are valuable active ingredients with hypotensive Effect. They inhibit the conversion of the decapeptide angiotensin I to angiotensin II and are therefore valuable Agents used to lower hypertension associated with angiotensin. Through the action of the enzyme renin Angiotensin I is produced on angiotensinogen, a pseudoglobulin in the blood plasma. Angiotensin I is produced by the angiotensin converting enzyme (ACE) converted into angiotensin II. The latter product is an active antihypertensive Substance that is causally related to various forms of hypertension in various mammals, like rats and dogs. The compounds of the invention intervene in the angiotensionogenic reaction sequence * (Renin) -> Angiotensin I ■ * (ACE) ■> Angiotensin II by inhibiting the angiotensin converting enzyme and the formation of the substance that increases blood pressure Reduce or prevent angiotensin II altogether. Thus, by administering an agent containing one or more compounds of the general formula I contains, which of angio-

Tensin-dependent hypertension in mammals is reduced. A single dose or preferably 2 to 4 divided over the day Doses, with daily doses 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 complied with, cause a

Lowering blood pressure. The means are preferred

administered orally. But it can also be administered parenterally, for example by subcutaneous, intramuscular, intravenous or intraperitoneal route.

The compounds of the invention can be used to treat

Hypertension also formulated along with a diuretic will. A combination product containing a compound of the invention and a diuretic can be

Mammals weighing 70 kg in total daily doses

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

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'for the compound of the invention and from about 15 to 300 mg and preferably about 15 to 200 mg for the diuretic are administered. Examples of diuretics that together which can be used with the compounds of the invention are thiazide diuretics such as chlorothiazide, hydrochlorothiazide, Flumethiazide, Hydroglumethiazide, Benzdroflumethiazide, Methchlothiazide, Trichloromethiazide, Polythiazide and benzothiazide, as well as etacrynic acid, Ticrynäfen, Chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of these compounds.

The compounds of general formula I can be converted into corresponding Dosage forms are packaged, for example into tablets, capsules or elixirs for the oral administration or to sterile solutions or suspensions for parenteral administration. About 10 to 500 mg of a compound of the general formula I or a mixture of such compounds are used together with

pharmacologically acceptable carriers, diluents, binders, preservatives, stabilizers, Flavors and the like processed into a unit dose, as it is per se in the pharmaceutical Practice is common. The amount of active ingredient in such preparations is chosen so that it corresponds to the aforementioned dosage range.

Embodiments:

³⁰ examples i

/ ~ 7 (S), 8S 7-7- (acetylthio) -2-methyl-1-oxopropyl 7-1, 4-dioxo-7-azaspiro /~H.H 7nonane-8-carboxylic acid a) N-carbobenzyloxy-H-hydroxy-L-proline

26.5 g (0.20 mol) 4-hydroxy-L-proline and 32.8 ml (0.23 Mol) benzyl chloroformate are dissolved in 200 ml of water

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and 100 ral acetone in the presence of 20 g (0.02 mol) potassium hydrogen carbonate and 69.2 g (0.50 mol) of potassium carbonate reacted and worked up with 90 ml of concentrated hydrochloric acid; see Can. J. Biochem. & Physiol., 37 (1959), pp.

584. N-carbobenzyloxy - ^ - hydroxy-L-proline is obtained. This Product is reacted with cyclohexylamine. 69 g of cyclohexylamine salt with a melting point of 193 ° to 195 ° C. are obtained. 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.

¹⁰ i> _ ~ D ⁶ = " ⁷⁰ ° (0 = 1%; chloroform).

b) N-carbobenzyloxy-iJ-keto-L-proline

21.5 g (0.81 moles) of N-carbobenzyloxy-4-hydroxy-L-proline will be used oxidized in 1.2 liters of acetone with 83 ml of 8 η chromic acid in sulfuric acid according to J.A.C.S., Vol. 79 (1957), p. 189. To facilitate the subsequent filtration of the chromium salts, add 30 g of diatomaceous earth (Celite) to the acetone solution given before the oxidizing agent is added. “An air stirrer is used for the conversion. 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 each time, over MgSO ₁ . dried and filtered off. After evaporation of the solvent, 22.8 g of N-carbobenzyloxy-4-keto-L-proline are obtained, which is crystallized from 50 ml of ether and 150 ml of hexane. 17.2 g (81 percent of theory) of product with a melting point of 99 ° to 101 ° are obtained.

3Q Ζά_

17 ° (c t 1%; chloroform).

c) N-carbobenzyloxy-4 _t 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. H ₂ O in 1.31 liters of benzene is heated with stirring. The resulting solution is under 7 hours

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Γ "1

Heated to reflux, the water formed being collected in an apparatus according to Dean-Stark. The mixture is left to stand at room temperature overnight. The lower glycol phase is separated off and the benzene solution is washed with 150 ml of saturated sodium chloride solution over MgSO ₁ . dried and evaporated. 14.6 g of N-carbobenzyloxy-4,4-ethylenedioxy-L-proline are obtained 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 inoculation and rubbing, the crystalline cyclohexylamine salt separates out. After standing in the cold is obtained 9.0 g of product, mp 179 to 18O ⁰ C (sintering 173) - The product is recrystallized from acetonitrile, after which the F. is 182 to 184 ° (179 ° sintering).

¹⁵ / ~ ck Ti ⁶ = -21 ° (c = 1%; ethanol).

8.4 g of the cyclohexylamine salt are dissolved in 40 ml of ethyl acetate suspended 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 each time. The combined organic phases are dried _{over MgSO 1.} The solvent is evaporated, the final pressure being 0.2 torr. The syrupy residue obtained begins upon arrival

** rub in diethyl ether to crystallize. After evaporation of the diethyl ether, 6.4 g (42 percent of theory) of N-carbobenzyloxy-4,4-ethylenedioxy-L-proline are obtained in the form an almost colorless product with a melting point of 101 to 103 ° C (sintering 98 ° C).

³⁰ Γα J * ⁶ = -34 ° (c = 1%; CHCl ,,).

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 methanol / water (2: 1)

is treated with 1 g of 5% palladium-on-carbon and

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Shaken in a Parr hydrogenator for 6 hours. The catalyst is filtered off under nitrogen and washed with methanol. The combined filtrates are evaporated, the final pressure being 0.1-0.2 torr. 1.7 g (94 percent of theory) of 4,4-ethylenedioxy-L-proline are obtained as a colorless solid from F. 245 to

247 ° C (dec.).

- -j-26 ~ _o o (c = 0.5%; 1: 1 methanol / water).

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

A solution of 3.2 g (0.0185 mol) of 4,4-ethylenedioxy-L-proline in 50 ml of water, the mixture is cooled to 5 ° C. while stirring, and solid sodium carbonate is added a little at a time

* ^{5 brought} the pH value 8.5. Then, with continued stirring and cooling, a solution of 3.7 g (0.020 mol) of D-3-acetylthio-2-methylpropanoyl chloride in 5 ml of diethyl ether is added in portions, the pH being adjusted by adding 25 percent sodium carbonate solution (about 14 ml ) is kept at 8.5. After 11/4 hours the solution is treated with 50 ml of ethyl acetate, stirred, cooled, carefully acidified to pH 2.0 with hydrochloric acid (1: 1) and saturated with sodium chloride. After the phases have been separated, the aqueous phase is extracted 3 times with 50 ml of additional ethyl acetate each time. The combined organic phases are dried _{over MgSO 1.} The solvent is evaporated, the pressure at the end being 0.2 mm. The solid residue is rubbed under diethyl ether. The evaporation process is repeated. 5.9 g (100 percent of th.) Γΐ (S), 8S_7-7-jT "3- (acetylthio) -2-methyl-1-oxopropyl_7-1,4-dioxo-7-azaspirq / 4.4 _7nonane-8-carboxylic acid with a melting point of 108 to 111 ° C.

This product is converted into the dicyclohexylamine salt with 3.4 g of dicyclohexylamine in 70 ml of ethyl acetate

L J

030028/0724

leads. After inoculation and grinding, the crystalline salt precipitates. After recrystallization from 95 ml of acetonitrile, 6.7 g of product is obtained, melting at 187-189 ⁰ C (sintering 184 ° C). - _T 25 - C ₀ O (c = 1%; ethanol).

The dicyclohexylamine salt is converted into the free acid by suspending it in ethyl acetate and treating with 75 ml of 10 percent potassium hydrogen sulfate solution and stirring until 2 phases are formed. After the phases have been separated, the aqueous phase is extracted 4 times with 75 ml of ethyl acetate each time. The organic phases are combined and dried over MgSO ₁ . dried. After evaporation of the solvent, 4.1 g of ΓΊ (S), 8S_7-7- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl_7-1,4-dioxo-7-aza-spirq / f ~ are obtained 4.4_7nonane-8-carboxylic acid as a colorless product from. M.p. 120 to 122 ° C (sintering 117 ° C).
/ ~ (X 7 ^ 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 7nonane-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_7-1,4-dioxo-7-azaspiro -.. / ~ 4.4_7nonan-8-carboxylic acid is added of example 1e the mixture is stirred for a few minutes in an ice bath and then for 2 hours under argon at room temperature the solution is then treated with 30 ml of ethyl acetate, cooled, stirred and ml with 16 hydrochloric acid (1: 1) acidified. The phases are separated. The aqueous phase is extracted twice with a further 30 ml of ethyl acetate. The ethyl acetate extracts are combined and _{dried over MgSO 1.} After evaporation of the solvent, / ~ 7 (S), 8S T- 7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro- / 4.4 / nonane-8-carboxylic acid as a solid residue.

030028/0724

Γ "I.

The product is rubbed 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. 2.7 g _r "7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro_ / ^ 4.4_ / nonane-8-carboxylic acid are obtained as a colorless solid with a melting point of 131 to 133 ° C (sintering 125 ° C). Γα_7ρ ⁵ = -66 ° (c = 1%; ethanol).

¹⁰ Example3

(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 grams (0.03 moles) of N-carbobenzyloxy-4-keto-15

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

The pale yellow solution is treated with 1.5 g of potassium carbonate and then with 30 ml of water while stirring. Of the Most of the solvent is removed using a rotary evaporator. The syrupy residue obtained is __ shaken out with 30 ml of water and 30 ml of chloroform. To

After separating the phases, the aqueous phase is extracted 3 times with 30 ml of additional chloroform each time. 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, 8.4 g (88 percent of theory) of N-carbobenzyloxy-4,4-dimethoxy-L-proline methyl ester are obtained.

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

35 8.4 g (0.026 mol) of the ester from (a) are dissolved in 80 ml of Me ^

ethanol, add dropwise at -1 to 4 ° C with 18 ml (0.036

030028/0724

^ Mol) treated 2 η sodium hydroxide solution and then left for 1 hour at 0 ⁰ C and overnight at room temperature. About half of the solvent is removed on a rotary evaporator. The remaining solution is diluted with 150 ml of water, washed with 100 ml of diethyl ether (the washing liquid is discarded), acidified to pH 2 with 63 ml of hydrochloric acid (1: 1) while cooling and extracted 4 times with 750 ml of ethyl acetate each time. The combined extracts are washed with 50 ml of saturated sodium chloride solution and dried over MgSO ₁ . dried. After evaporation of the solvent, 8.0 g of a pale yellow, viscous oil are obtained. 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 inoculation and grinding, crystalline N-carbobenzyloxy-4,4-dimethoxy-L-proline-cy-

clohexylamine salt. After chilling overnight, it gets 7.0

fKJT

one 7.0 g of product with a mp of 157 to 159 ° C (sintering 151 ° C).

jfKJTn ⁼ ~ ^ ° (° ~ ¹ ° / ° ^{; Ätnano1} ) This material is recrystallized from 100 ml of acetonitrile. Of a colorless solid, mp 158 to 16O ⁰ C (sintering 154 ° C) is obtained in the salt form.
JjxJ ^ = -33 ° (c = 1%; ethanol).

The N-carbobenzyloxy-4,4-dimethoxy-L-proline cyclohexylamine salt is suspended in 40 ml of ethyl acetate, stirred and treated with 25 ml of 1 η hydrochloric acid. After two clear phases appear, the phases are separated. The aqueous phase is extracted 3 times with 40 ml of additional ethyl acetate each time. The combined organic phases are over MgSO ₁ . dried. The solvent is evaporated to a final pressure of 0.2 torr at 40 °. 7.2 g (70 percent of theory) of N-carbobenzyloxy-4,4-dimethoxy-L-proline are obtained as a pale yellow viscous syrup.
35

c) 4,4-dimethoxy-L-proline

A solution of 72 g (0.022 moles) of N-carbobenzyloxy-4,4-dimethoxy-L-proline in 210 ml of methanol / water (2: 1)

treated with 2.3 g of 5% palladium-on-carbon and 6 5

Shaken in a Parr hydrogenator for hours. The catalyst is filtered off under nitrogen and washed with methanol washed. The combined filtrates are evaporated, the pressure at the end being 0.1 to 0.2 torr.

A partially crystalline residue is obtained. This 10

The residue is taken up in 200 ml of methanol. The evaporation process will be repeated. When rubbing the solid under diethyl ether (the evaporation process is repeated) 3.6 g (95 percent of theory) of 4,4-dimethoxy-L-proline are obtained as an almost colorless solid with a melting point of 192 ° to 194 ° C.

(Decomposition).

£ c <J p ⁶ = -47 ° (c = 1%; methanol).

After recrystallization of a sample from methanol / diethyl ether he
(Decomposition).

ether gives a colorless product with a melting point of 197 to 198 ° C 20

L Ci- ⁷ D ⁼ "^ ^{9 (c = 1} * ^{; Methano1} ) ·

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

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

030Ü28 / 0724

- ⁴³ - 295120ο " ¹

chilled. The solution is then washed with 50 ml of ethyl acetate (the washing liquid is discarded) 50 ml of ethyl acetate, cooled, stirred, carefully adjusted to pH 2.0 with hydrochloric acid (1: 1).

** acidifies and saturated with sodium chloride. After the phases have been separated, the aqueous phase is extracted 3 times with 50 ml of additional ethyl acetate each time. The organic phases are combined and _{dried over MgSO 1.} The solvent is evaporated, the pressure at the end being W 0.2 Torr 6.7 g of a syrupy product are obtained. This syrup is treated with 3.9 g of dicyclohexylamine in 70 ml of ethyl acetate to give 6.5 g of colorless (S) - W ~ 3- (acetyl thio) -2-methyl-1- oxo pr OPyI _- J ¹ *, 4-dimethoxy-L-proline dicyclohexylamine salt in 2 yields of 3.1 and 3.4 g. The temperature is 158 to 160 ° C (sintering 145 ° C). rbf_7p ⁶ = - 71 ° (c = 1%; ethanol).

After recrystallization from 20 ml of hot ethyl acetate / 60 ml of hexane, 6.0 g of colorless salt with a melting point of 158 to 166 ° C. (sintering 155 ° C.) are obtained.
ΰΰψ = -69 ° (c = 1%; ethanol).

The dicyclohexylamine salt is converted into the free acid by suspending 5.0 g of the salt in 50 ml of ethyl acetate. The suspension is cooled and treated with 60 ml of 10 percent strength potassium hydrogen sulfate solution. Two clear phases are obtained. After the phases have been separated, the aqueous phase is extracted 3 times with 50 ml of ethyl acetate each time. The combined organic phases are dried _{over MgSO 1.} The solvent is evaporated to a final pressure of 0.1 to 0.2 Torr at 45 °. M, 1 g (69 percent of theory) of (S) -W ~ 3- (acetylthio) -2-methyli-oxopropyl ^ / - ¹ *, 4-dimethoxy-L-proline is obtained in the form of a viscous, almost glassy Materials.
i ~ oC_7p ⁵ = -112 ° (c = 1%; ethanol).

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Γ

1 example4

(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 to 4.1 g (0.013 mol) of (S) -1- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl-7-4,4-dimethoxy-L-proline while cooling and under argon. The mixture is stirred in an ice bath, a pale yellow solution forming after about 15 minutes. The mixture is then stirred for a further 2 hours under argon at room temperature. The solution is then extracted with 30 ml of ethyl acetate. This operation and the following measures are carried out under argon as far as possible. The aqueous phase is stirred, cooled, covered with 30 ml of ethyl acetate and acidified in portions with about 16 ml of hydrochloric acid (1: 1). After the phases have been separated, the aqueous phase is extracted 3 times with 30 ml of additional ethyl acetate each time. The combined ethyl acetate phases are dried _{over MgSO 1.} After evaporation of the solvent, 3.5 g (100 percent of the theory) of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline are obtained as a colorless, viscous syrup.

25 _ /. <* _ / Β = -72 ° (c = 1%; ethanol).

3.4 g of the last-named product are treated with 20 ml of ethyl acetate, ground, diluted with 30 ml of hexane and cooled. This gives 2.6 g of a colorless solid substance, melting at 108 to 11O ⁰ C.

MY_7p ⁵ = -77 ° (c = 1%; ethanol).

Example 5

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

a) N-carbobenzyloxy-4,4-diethoxy-L-proline-ether

030028/0724

Γ Π

Geraäss Example 3 fa) are using triethyl orthoaric acid instead of trimethyl orthoformate and using ethanol instead of methanol 10.8 g of N-carbobenzyloxy-4,4-diethoxy-L-proline ethyl ester obtained in the form of a yellow oil.

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

10.8 g (0.03 mol) of the crude ester from part (a) are mixed according to Example 4 (b) with 70 ml of sodium hydroxide solution saponified. After adding 30 ml of ethanol in portions of per 10 ml a solution is obtained which gives 10.5 g of a yellow viscous oil. This oil is in 100 ml of diethyl ether dissolved and treated with 3.0 g of cyclohexylamine. After inoculation and grinding, 8.3 g of crystalline N-carbobene-15 are obtained

zyloxy- ^ jU-diethoxy-L-proline-cyclohexylamine salt with a temperature of 123 to 126 ° C (sintering 114 ° C).
Λ * _7ρ ⁶ = -32 ° (c = 1%; ethanol).

This material is recrystallized from 20 ml of acetonitrile, to give 7.0 g of colorless salt, mp 125 to 128 ° C (sintering 115 ⁰ C).
_ / "ö_7p ⁶ = -31 ° (c = 1%; ethanol).

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

Q ₀ ganischen phases are combined and over MgSO ₁ . dried. After evaporation of the solvent, 5.6 g (56 percent of theory) of N-carbobenzyloxy-4,4-diethoxy-L-proline are obtained as a pale yellow oil.

35 c) 4,4-diethoxy-L-proline

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

J 030028/072 / *

ethoxy-L-proline in 18Ο ml ethanol / water (2: 1) is with Treated 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 rubbed first under ethanol and then under diethyl ether, the EinäampfVorgang is repeated in each case. 3 g are obtained (91 percent of theory) 4,4-diethoxy-L-proline as an almost colorless solid with a temperature of 172 to 174 ° C (decomposition; previously gradual Darkening and sintering).

10 Γ « J ²⁶ =
-D : -40 ° (c = 1%; methanol). H 6, N CgH 17 ^NO 4 . O ₁ 25 H ₂ O _c 8.49 6, 74 calc .: 52.03 8.59 69 found: 52.22 7-4, 15th 1-oxopropyl 4- d) (S) _1 - / ~ 3- (Acetyl thio) -2-methyl- diethoxy-L-proline

2.9 g (0.014 moles) 4,4-diethoxy-L-proline from part (c) and

3 g (0.017 mole) D-3-acetylthio-2-raethylpropionyl chloride 20th

are dissolved in 3.5 ml of diethyl ether and reacted in 35 ml of water in the presence of sodium carbonate according to Example 3 (d). 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. 4.9 g of (S) -1 -_ / _ "" (3-acetylthio) -2-methyl-1-oxopropyl_ / - 4,4-diethoxy-L-proline-dicyclohexylamine salt with a melting point of 135 are obtained in 2 yields up to 138 ⁰ C (sintering 132 ° C). After recrystallization from 15 ml of hot ethyl acetate / 45 ml of hexane, 4.2 g of crystalline colorless salt with a melting point of 138 to 140 ° C. (sintering 135 ° C.) are obtained. HxJ ^ = -63 ° (c = 1%; ethanol).

35

C ₁₅ H ₂₅ NO ₆ S.

N C. 33 9 H 5 N 6th S. ber .: 61, 48 9 , 15 5 , 30 5 , 06 found : 61, , 55 , 25 , 91

030028/0724

The dicyclohexylamine salt is converted into the free acid by suspending 1.2 g of the salt in 40 ml of ethyl acetate. The suspension is cooled and treated with 40 ml of 10 percent strength potassium hydrogen sulfate solution. S 2 phases are obtained. After the phases have been separated, the aqueous phase is extracted 3 times with 50 ml of ethyl acetate each time. The combined organic phases are over MgSO ₁ . dried. After evaporation of the solvent, 3.0 g (61 percent of theory) of (S) -W ~ 3- (acetylthio) -W 2-methyl-1-oxopropyl-7-4,4-diethoxy-L-proline are obtained as 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, with cooling and under argon, to 3 »0 g (0.0086 mol) of (S) -1W ~ 3- (acetylthio) -2-methyl-1-oxopropyl-7-4,4-diethoxy-L-proline . The mixture is worked up according to Example 4. 2.4 g (92 percent of theory) of (S) -4,4-diethoxy-1- (3-mercapto) -2-methyl-1-oxopropyl) -L-proline are obtained as an almost colorless, viscous syrup. / öc7p ⁶ = -64 ° (c = 1%; ethanol).

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

Example 7

/ "" 2 (S). 3S 7-2- / ~ 3-fAcetylthio) -2-methyl-1-oxopropyl 7-6.10-dioxo-2-azaspiro / ~ 4.5 7-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) 1,3-propanediol in 450 ml Benzene is obtained in the presence of 500 mg of p-toluenesulfonic acid

030028/0724

one 12.3 g of a crude viscous ester. This product is saponified with 70 ml of 1 η sodium hydroxide solution. Man receives 10.6 g of N-carbobenzyloxy-4,4-trimethylenedioxy-L-proline in the form of a yellow oil. This oil comes in 40 ml Dissolved ethanol / 400 ml of diethyl ether and treated with 3.2 g of cyclohexylamine. 10.1 g of N-carbobenzyloxy-4,4-trimethylenedioxy-L-proline cyclohexylamine salt are obtained from 163 to 165 ° C (sintering 160 ° C).

/ otT ^ = -27 ° (c = 1%; ethanol). After crystallization of 9.8 g of this salt from 300 ml of acetonitrile, 9.5 g of a colorless cyclohexylamine salt with a melting point of 165 to 167 ° C. (sintering 162 ° C.) are obtained.
/."o<_7p ⁵ = -27 ° (c = 1%; ethanol.

^ ⁵ 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 1 η hydrochloric acid. After the phases have been separated, the aqueous phase is extracted 3 times with 40 ml of additional ethyl acetate each time. The organi-

^ see phases are combined and over MgSO ₁ . dried. After evaporation of the solvent, 7.1 g (75 percent of theory) of N-carbobenzyloxy ^^ - trimethylendioxy-L-proline are obtained in the form of a glass-like product.

^25th b) 4 _{tons of} 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 in the presence of 2 g of 5% palladium-on-carbon

"Hydrogenated. 3.8 g (93 percent of theory) of 4,4-Trime-30 are obtained

ethylenedioxy-L-proline in the form of an almost bare-bones solid with a temperature of 234 to 236 ° C (dec; before gradual darkening and sintering).
Z ^- OL ⁷ D ⁵ = -36 ° (c = 0.5%; methanol / water = 1: 1).

C ₈ H ₁₃ NO ₄ 51 C. 7th H 7th N ber .: 51 , 33 7th , 00 7th , 48 found: , 42 , 11 , 40

030028/0724

- ^49; - 295120ο " ¹

M / ~ 2 (S), 3S 7-2- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl7-6,10-dioxo-2-azaspiro / ~ 4,5 / decane-3-carboxylic acid

3> 7 g (0.02 mol) 4,4-trimethylenedioxy-L-proline are with 4.0 g (0.022 mol) D-S-acetylthio - ^ - methylpropionyl chloride acylated in 50 ml of water in the presence of sodium carbonate according to Example 1 (e). 7.3 g of a vitreous are obtained Raw product.

This product is made with 3.6 g of dicyclohexylamine in 70 ml of 10

Ethyl acetate converted into the dicyclohexylamine salt. After inoculation and grinding, the crystalline salt precipitates. This gives 7.5 g of dicyclohexylamine salt, mp 170 ⁰ C (sintering 166 ° C).

/ ~ oi 7 ^ ⁶ = -59 ° (c = 1%; ethanol) 15 - - ^

After recrystallization from 30 ml of acetonitrile, 6.5 g are obtained

colorless salt from 169 to 171 ⁰ C. Γοίΐψ = - 63 ° (c = 1%; ethanol).

The dicyclohexylamine salt is converted into the free acid by suspending 6.4 g of the salt in 75 ml of ethyl acetate and treating with 75 ml of 10 percent potassium hydrogen sulfate solution while stirring until 2 phases are formed. After the phases have been separated, the aqueous phase is extracted 4 times with 75 ml of ethyl acetate each time. The organic phases are combined and dried _{over MgSO 1.} After evaporation of the solvent, 4.3 g (67 percent of th.) ^ "2 (S), 3S_7-2- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl _ / - 6,10- dioxo-2-azaspiro ^ 4,5_ / decane-3-

carboxylic acid. in the form of a glass-like product. 30th

Example 8

/ ~ 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 _ / ~ 2 (S), 3S_7-2-_ / 73-acetylthio) -2-methyl-1-oxopropyl _ / - 6,10-dioxo-2-azaspiro ^ 4,5_ / decane-3-carbon-

030028/072 / * ^J

Γ

acid are hydrolyzed according to Example 2 with 8.5 ml of concentrated ammonia in 20 ml of water. 0.9 g of a colorless solid is obtained.
CcxJ ^ = -64 ° (c = 0.5%; ethanol).

Another 0.8 g of product is obtained by extracting the aqueous Phase with chloroform.

JC & JTJ ³ = -66 °. The two yields are dissolved in chloroform, evaporated and rubbed under diethyl ether. After repeated evaporation, 1.7 g (46 percent of theory) / ~ 2 (S), 3S_7-2- (3-mercapto-2-methyl-1-oxopropyl) -6,10-dioxo-2-azaspiro are obtained ^ 4 ~, 57decane-3-carboxylic acid with a melting point of 169 to 171 ° C.

( Sintering 167 ° C). ( C. = 1%; Methanol H ). 4th N 1 1 S. L. ~ α 7 ²⁶ = -71 ° C. , 62 4th , 84 1 1 , 08 C. ₁₂ H ₁₉ NO ₅ p 49 , 81 6th , 67 , 93 , 10 ber .: 49 , 67 6th found:

Example 9

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

—Z ^- ^ Z

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 with stirring with 3 ml (0.036 mol) of ethanedithiol, cooled to 8 ° and with 3 ml (0.024 mol) of boron trifluoride etherate treated. After removing the cooling bath, the pale yellow solution is stirred for a further hour and then left at room temperature overnight. The solution is then stirred, treated with several pieces of crushed ice and then treated with 20 ml of water. After 30 minutes the phases are separated. The aqueous phase (50 ml) is extracted 3 times with 30 ml of additional methylene chloride each time. 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

030028/0724

a rotary evaporator gives 6 g (100 percent of theory) of N-carbobenzyloxy-4,4-ethylenedithio-L-proline methyl ester in the form of a pale yellow oil.

⁵ b) N-carbobenzyloxy-4,4-ethylenedithio-L-proline

7.1 g (about 0.018 mol) of the methyl ester from part (a) are dissolved in 65 ml of methanol. The solution is added dropwise at -1 to 4 ° C with 14.5 ml (0.029 mol) of 2 η sodium hydroxide solution and was then stirred for 1 hour at 0 ⁰ C and about 10

Left to stand overnight at room temperature. Then about half of the solvent is removed using a rotary evaporator removed. The remaining solution is diluted with 125 ml of water and washed with diethyl ether (the washing liquid is discarded), while cooling with 5 ml of salt IS

acid (1: 1) acidified to pH 2 and extracted 4 times with 50 ml of ethyl acetate each time. The combined extracts are washed with 50 ml of saturated sodium chloride solution and dried over MgSO ₁ . dried. After the

6 g of a pale yellow viscous 20 are obtained from the solvent

Oil. This oil is dissolved in 25 ml of ethanol with 1.8 g Treated cyclohexylamine in 5 ml of ethanol and diluted with 300 ml of diethyl ether. When inoculating and rubbing it falls crystalline cyclohexylamine salt. After cold spots over

__ night one receives 5.7 g of N-carbobenzyloxy-4,4-ethylenedithio-

ο L-proline cyclohexylamine salt from temperature 205 to 207 (sintering 201 °). After recrystallization from 50 ml of ethanol / 400 ml of diethyl ether is obtained 4.9 g colorless salt, mp 207 to 209 ° C (sintering 201 ⁰ C).
/."c<_7Jp = -15 ° (c = 1%; chloroform).

4 _t 8 g of the cyclohexylamine salt are suspended in 25 ml of ethyl acetate, stirred and treated with 25 ml of 1 η hydrochloric acid. After 2 clear phases have formed, the phases are separated. The aqueous phase is extracted 3 times with 25 ml of additional ethyl acetate each time. The Ver

030028/0724

Γ Π

* Unified organic phases are poured over MgSO ₁ . dried. After evaporation of the solvent, 3 _f 8 g (62 percent of theory) of N-carbobenzyloxy-4,4-ethylenedithio-

L-proline as a pale yellow viscous syrup. 5

c) 4,4-ethylenedithio-L-proline hydrobromide

3.7 g (0.011 mol) of N-carbobenzyloxy-4,4-ethylenedithio-L-proline are mixed with 20 ml of hydrogen bromide in acetic acid

(30 to 32 percent) treated, loosely closed and rated 10

stirred with a magnetic stirrer. Mixing turns out due to the viscosity of the starting material is difficult. The starting material is as far as possible with a spatula broken up. A crystalline product begins to separate out. Additional amounts of hydrogen bromide in acetic acid are added after 15 minutes (10 ml) and after 25 minutes (5 ml). Then it becomes up to a total time stirred for 35 minutes. The precipitation of the product is completed by adding 250 ml of diethyl ether. After 15 minutes of cooling, the cream-colored ma-

filtered off under nitrogen, treated with diethyl ether

urri under reduced pressure
wash and / dry. This gives 2.7 g of 4,4-Xthylendithio-L-proline hydrobromide, mp 240-242 ⁰ C (dec .; sintering and darkening from about 200 ⁰ C).
Πχ_7 ^ ⁶ = -40 ° (c = 0.5%; chloroform / methanol = 1: 1).

d) / ~ 7 (S) _t 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) 4,4-Xthylenedithio-L-proline hydrobromide in 25 ml of water is cooled to 5 ° C and by adding a 25 percent sodium carbonate solution (W / v) brought to pH 8.2. With continued stirring and cooling, a solution of 1.9 g (0.01 mol) D-3-acetylthio-2-methylpropionyl chloride in 2.5 ml of diethyl ether was added in portions, the pH being reduced by dropwise Addition of 25 percent sodium carbonate solution

L J

030028/0724

is kept in the range of 7.5 to 8.2. After the pH has stabilized in the range from 8.2 to 8.5 (after about 15 minutes), stirring and cooling are continued (1 hour in total). The solution is then washed with 25 ml of ethyl acetate (the washing liquid is discarded), covered with 25 ml of ethyl acetate, cooled, stirred, carefully acidified to pH 2.0 with hydrochloric acid (1: 1) and saturated with sodium chloride. After the phases have been separated, the aqueous phase is extracted 3 times with 25 ml of additional ethyl acetate each time. The combined organic phases are dried _{over MgSO 1.} The solvent is evaporated, the final pressure being 0.2 torr. 2.6 g of a syrupy product are obtained which begins to crystallize. This product comes in 30 ml

° ethyl acetate treated with 1.5 g of dicyclohexylamine. 3.0 g of colorless dicyclohexylamine salt with a ^{melting point of 176 to 178 °} C. (sintering 170 ^° C.) are obtained.

/ ~ «7? = -55 ° (c = 1%; ethanol). This product is triturated with 15 ml of acetonitrile in a mortar, cooled for 1 hour, filtered and washed with 5 ml of cold acetonitrile and with diethyl ether. This gives 2.9 g of dicyclohexylamine salt, mp 177-179 ° C (sintering 172 ⁰ C). ΓΌ <_7ρ ⁶ = -56 ° (c = 1%; ethanol).

²⁵ C ₁₃ H ₁₉ NO ₄ S. C.

₂₃ N. C. , 56 7th H 5 N S. 12th ber .: 56 , 21 8th , 98 5 , 28 18 00 found : 56 , 18 , 05 18

The aforementioned dicyclohexylamine salt is converted into the free acid by adding 2.8 g of salt to 30 ml of ethyl acetate suspended. The suspension is cooled and treated with 30 ml of 10 percent strength potassium hydrogen sulfate solution. Man receives 2 clear phases. After the phases have been separated, the aqueous phase is ex-

traced. The combined organic phases are over

030028/0724

* MgSO ₁ . dried. The solvent is evaporated, whereby

at the end there is a pressure of 0.1 to 0.2 Torr at 45 °. 2.0 g (63 percent of the theory) /.T(S), 8S_7_7_ / ~ 3_ are obtained (Acetylthio) -2-methyl-1-oxopropyl_7-7-aza-1,4-dithiaspiro / 4-4_7-nonane-8-carboxylic acid as a colorless solid with a melting point of 125 to

126 ° C (sintering 122 °).

_ / "oc_7p ⁶ = -101 ° (c = 1%; ethanol).

Example 10

¹⁰ / ~ 7 (S), 8S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -7-aza-1,4-dithiaspiro / 4.4 / nonane-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 under cooling and under argon to 1.9 g (0.0054 mol) / "7 (S), 8S_7-7 -_ / ~~ 3- (Acetylthio) -2-methyl-1-oxopropyl_7-7-aza- 1,4-dithiaspiro_ / ~ 4.4_7nonane-8-carboxylic acid given. The mixture is stirred in an ice bath until a solution results. Then another 2 hours under argon at room temperature touched. The solution is then extracted with 15 ml of ethyl acetate under argon. The watery Phase is cooled, stirred, covered with 15 ml of ethyl acetate and in portions with about 6.5 ml of hydrochloric acid (1: 1) acidified. The phases are separated. The watery

Phase is 3 times with 15 ml of additional ethyl acetate

ester extracted. The combined ethyl acetate phases are dried _{over MgSO 1.} After evaporation of the solvent, a glassy residue is obtained which solidifies on trituration under diethyl ester. The evaporation process is repeated. The resulting colorless product becomes

suspended in 30 ml of hexane, filtered and reduced under reduced pressure Print dried. 1.4 g (84 percent of theory) _ / ~ 7 (S), 8s_7-7- (3-mercapto-2-methyl-1-oxopropyl) -7-aza-1,4-dithiaspiro ^ are obtained 4.4_ / nonane-8-carboxylic acid from a temperature of 116 to 118 ° C (sintering 105 ° C).

£ ~ oU ^ ⁶ = - ⁴ ^ ⁰ (c = 1%; ethanol).

030028/0724

3 42 C. 5 H ber .: 42 , 97 5 , 57 found: , 70 , 71

N S SH 4.56 31.29 100% 4.54 31.16 100%

Example 11

_t 8S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -1 _t 4-dioxo-7-azaspiro / ~ 4 «5 7-decane-8-carboxylic acid

a) / * ~ 7 (S), 8S 7-7- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl 7-1.4 -dioxo-7-azasDiro / ~ 4.5 7dec an-8- carbonic acid

to - * ^c ■ ^!

According to Example 1, using an equivalent Amount of N-carbobenzyloxy-5-keto-L-pipecolic acid instead of N-carbobenzyloxy-4-keto-L-proline in part (c) and then according to 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 produced.

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 according to Example 2 with concentrated Hydrolyzed ammonia. One obtains / ~~ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro- _ / _ 4.5_ / decane-8-carboxylic acid.

Example 12

, 2S 7-1- (3 "mercapto-2-methyl-1-oxopropyl) -5,5-dimethoxy-2-piperidinecarboxylic acid a) / ~ 1 (S), 2S 7-1- / ~ 3- (acetylthio-2-methyl-1-oxopropyl. 7- 5,5-dimethoxy-2-p'i per idi near bonsäure

Following the procedure of Example 3, using N-carbobenzyloxy-5-keto-L-pipecolic acid instead of N-carbobenzyloxy-4-keto-L-proline in part (a) _ / ~ 1 (S), 2S_7-W ~ 3- (acetyl thio) -2-methyl-1-oxopropyl_7-5.5

dimethoxy-2-piperidinecarboxylic acid.
35

C3CC28 / 072A

Γ "1

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 according to Example 4 with concentrated Hydrolyzed ammonia. One obtains £ ~~ 1 (S), 2S_7-1- (3-merc'apto-2-methyl-1-oxopropyl ) -5,5-dimethoxy-2-piperidinecarboxylic acid.

Example 13

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

10 ^c * ^c "'

dimethoxy-2-piperidinecarboxylic acid

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

According to Example 3, using an equivalent amount of N-carbobenzyloxy-4-keto-2-pipecolic acid instead of N-carbobenzyloxy-iJ-keto-L ^ -proline in part (a) / ~ 1 (S), 2i_7- 1-_ / ~ 3- {acetylthio) -2-methyl-1-oxopropyl_7- ^l , U-dimethoxy-2-piperidinoic acid.

b) / ~ 1 (S) , 2- 7-1- / ~ 3-mercapto-2-methyl-T-oxopropyl) -U, 4-dimethoxy-2-piperidine-carboxylic acid

The product of part (a) is hydrolyzed according to Example 4 with concentrated ammonia. Obtained l_ 1 (S), 2 -_ / - 1-2_ (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-2-piperidinecarboxylic acid.

Example 14

/~2(S).3S 7-2- (3-mercapto-2-methyl-1-oxopropyl) -6.10-di- 30 thia-2-azaspiro / ~ 4.5 7-decane-3-carboxylic acid

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

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

030028 / 072A

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

The product of part (a) is made according to the procedure of Example 10 hydrolyzed with concentrated ammonia. This gives _ / ~ 2 (S), 3S_7-2- (3-mercapto-2-methyl-1-oxopropyl) -6,10-dithia-2-azaspiro / ~~ 4.5_7decane-3-carboxylic acid.

Example 15

/ ~ 7 (S), 8S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -1-oxo-4-thia-7-azaspiro / ~ 4.4 7nonane-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, using 2-mercaptoethanol instead of ethylene glycol in part (c) / ~ 7 (S), 8S J- 1-J_ 3- (acetylthio) -2-methyl-1 -oxopropyl __ / - 1 -oxo -4-thia- ^- M. 47nonane-8-carboxylic acid.

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

The product of part (a) is hydrolyzed according to Example 2 with concentrated ammonia. L_ obtained 7 (S), 8S __ / - 7- (3-mercapto-2-methyl-1-oxopropyl) -1-oxo-4-thia-7-azaspiro] _ 4.4_ / nonane-8-carboxylic acid.

Example 16

(8S) -7- / ~ 3- (acetylthio) -2-trifluoromethyl-1-oxopropyl 1- 1,4-dioxo-7-azaspiro / ~ 4.4 / nonane-8-carboxylic acid (Isomers A and B)

30 a) D, L-3- (Acetylthio) -2-trifluoromethylpropionic acid

10 g (0.071 mol) of iX-trifluoromethylacrylic acid (prepared according to J.Chem. Soc, 1954, p. 371) are cooled in a salt / ice / water bath and added in portions while stirring

5.7 ml (0.075 mole) of 97 percent thiolacetic acid. 35

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

030028/0724

Cold stirred. The mixture is then left on Warm up to room temperature. The distillation gives 14 g (91 percent of theory) D, L-3- (acetylthio) -2-trifluoromethylpropionic acid as a light yellow oil of bp 149 to 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 removing the excess thionyl chloride using a rotary evaporator is distilled. This gives 6.8 g of D, L-3- (Acetylthio) -2-trifluormethylpropionylchlorid as a light yellow oil, bp. 80 to 82 ⁰ C / 16 Torr.

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

( Isomers A and B) 20

2.4 g (0.014 mol) of 4,4-ethylenedioxy-L-proline are mixed 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 the example 1 (e) implemented. This gives 4.5 g of a nearly colorless solid, mp 126-145 ° C (sintering 115 ⁰ C).
/ ~ k 7J; 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 air-dried. 2.7 g of product with a melting point of 166 to 172 ° C. (sintering 140 ° C.) / * 7; are obtained; ⁵ = -62 ° (c = 1%; ethanol).

This material is then placed in a mortar with 25 ml of diethyl ether grind, after 15 minutes filtered, with something

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- ⁵⁹ - 295120ο " ¹

Washed diethyl ether and allowed to air dry again.

2.1 g of product with a melting point of 172 to 177 ° C. (sintering 143 ° C.) are obtained. After crystallization from 11 ml of boiling isopropanol and cooling overnight, 1.55 g of (8S) -7- / ~ 3- ^s (acetylthio) -2-trifluoromethyl-1-oxopropyl-7-1,4-dioxo-7-azaspiro are obtained £ ~ 4.4_7nonan-8-carboxylic acid (isomer A) as a colorless solid, mp 192-194 ° C (sintering 183 ⁰ C).
Γ * Τΐ ⁵ = -32 ° (c = 1%; ethanol).

A sample recrystallized from isopropanol has a temperature of 193 to 195 ° C (sintering 184 ° C).
£ ~ <Χ_7 ^ ⁵ = -134 ° (c = 1%; ethanol).

Isomer B is obtained by combining the aforementioned diethyl ether and isopropanol filtrates. After removing the solvents under reduced pressure, 2.2 g of a pale yellow solid with a melting point of 108 to 109 ° C. (sintering 95 ° C.) are obtained.
/ ~ <x_7p ⁵ = + 30 ° (c = 1%; ethanol).

This material is crystallized from 6 ml of iso-

purified propanol. 1.2 g of an almost colorless one are obtained

Solid, mp 153-155 ° C (sintering 130 ⁰ C).

_ / ~ * _7Jp = + 40 ° (c = 1%; ethanol). After crystallization from 4 ml of ethyl acetate / 6 ml of hexane are obtained 1.1 g

(8S) -7- / ~ 3-acetylthio) -2-trifluoromethyl-1-oxopropyl 7-

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

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

_ / "~ Λ_7ρ ⁵ = + 41 ° (c - 1%; ethanol).

Example 17

(8S) -7- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -1,4-

dioxo-7-azaspiro / ~ 4.4 7nonane-8-carboxylic acid (isomer A)

1.45 g (0.0039 mol) of isomer A from Example 16 are hydrolyzed in accordance with Example 2 for 1 hour with 2.5 ml of concentrated ammonia in 6 ml of water. You get 1 _? 25 g (97 percent

030028/0724

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

Γ Π

d. Th.) (8S) -7- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / ~ 4. 4_7nonane-8-carboxylic acid (isomer A) as a glassy product. Γ «7» ⁵ = -61 ° (cr 1%; ethanol).

Thin layer chromatography: R _f value 0.40 (95: 5: 5 = methylene chloride: methanol: acetic acid; visualization of SH reagent, PMA and warming).

The aforementioned acid is dissolved in ethyl acetate and treated with 1-adamantanamine. The 1-adamantanamine salt is obtained with a melting point of 213 to 215 ° C. (decomp.).
/ 7 ° i_7p ⁵ = -47 ° (c = 1%; methanol).

Example 18

(8S) -7- (2-mercapto-2-trifluoromethyl-1-oxopropyl) -1,4-dioxo-7-azaspiro / ~ 4.4 ~ nonane-8-carboxylic acid (Isomer B)

1.05 g (0.0028 mol) of isomer B from Example 16 are hydrolyzed according to Example 2 with 2 ml of concentrated ammonia in 5 ml of water. 0.9 g (97 percent of theory) of (8S) -7- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -1,4-dioxo-7-azaspirc7 ~ 4.4_7nonane-8-carboxylic acid are obtained (Isomer B) as a pale yellow viscous syrup.
/ ~ cX_7 _D = -16 ° (c = 1%; ethanol). The material solidifies

to a waxy solid with a melting point of 61 to 64 ° C (Sin-

tern 1 55 ⁰ C). . 0 , 25 H 0
S. C. , 58 4th H 4th N 9 S. 17th F. C ₁₁ H 4 ^F 3NO ₅ p ber. : 39 , 60 4th , 38 4th , 20 9 , 61 16 , 01 found : 39 , 28 , 26 , 62 , 89

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- ⁶¹ - 295120 ο " ¹

¹ example 19

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

(Isomers A and B)

According to Example 16, 4,4-dimethoxy-L-proline is used instead of 4,4-ethylenedioxy-L-proline in part (c) 1 -_ / ~ 3- (acetylthio) -2-trifluoromethyl-1-oxopropyl-7-4,4-dimethoxy-L-proline as a racemic mixture. According to Example 16, this mixture can be converted into the individual isomers be separated.

Example 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.
20th

Example 21

, 8S 7-7- (3-mercapto-2-mercaptomethyl-1-oxopropyl) -

4.4 / nonane-8-carboxylic acid

a) / ~ 7 (S), 8S 7-7- / ~ 3- (acetylthio) -2- (acetylthiomethyl) -1-oxopropyl 7-1,4-dioxo-7-azaspiro / ~ 4 .4 7nonane-8 -carbon-

acid

Geraäss Example 1 is obtained using D-2-acetylthiomethyl-3-acetylthiopropionyl chloride instead of D-3-acetylthio-2-methylpropionyl chloride in part (e) / ~ 7 (S), 8S_7-7- / ~ 3- (Acetylthio) -2- (acetylthiomethyl) -1-oxopropyl_7-1,4-dioxo-7-azaspirq / ^ 4.4_ / nonane-8-carboxylic acid.

b) / ~ 7 (S), 8 S 7-7- (3-mercapto-2-mercaptomethyl-1-oxo-

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

The product of part (a) is according to Example 2 with concentrated Hydrolyzed ammonia. One obtains / ~ 7 (S), 8s7-

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" ⁶² '295120ο" ¹

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

Example 22

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

a) (S) -1- / ~ 3- (Acetylthio) -2- (acetylthiomethyl) -1-oxopropyl 7-4,4-dimethoxy-L-proline

10 Device Example 3 is obtained using D-2-

Acetylthiomethyl-3-acetylthiopropionyl chloride instead of D-3-acetylthio-2-methylpropionyl chloride in part (d) (S) -1- £ ~ 3- ( acetylthio) -2- (acetylthiomethyl) -1-oxopropyl_7-4,4-dimethoxy -L-proline.

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

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

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

Example 23

(8S) -7- (3-mercapto-2-methy1thio-1-oxopropyl) -1,4-dioxo-7-azaspiro / 4.4 7nonane-8-carboxylic acid 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., Chemical Reports, Vol. 94 (1916), pp.

3254) are with ice cooling with 94 ml 1 η aqueous sodium hydroxide solution touched. The mixture is then allowed to warm to room temperature and is stirred for 5 hours. the The solution obtained is washed with diethyl ether and then adjusted to pH with concentrated hydrochloric acid

35 2 acidified. The solid precipitate is extracted into methylene chloride. The solution is washed with saturated sodium

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- 63 - 295120 ο " ¹

'washed trium chloride solution. After evaporation of the solvent 2- (methylthio) acrylic acid is obtained as a solid residue with a melting point of 70 to 75 ° C, which is immediately followed by the following Implementation is used.

Xquimolare amounts of 2- (methylthio) acrylic acid and thiolacetic acid are mixed under argon and stirred for several hours at 80 ⁰ C. 3- (Acetylthio) -2- (methyl-

thio) propionic acid. 10

b) 3- (Acetylthio) -2- (methylthio) propionic acid chloride

3- (Acetylthio) -2- (methylthio) propionic acid is refluxed in thionyl chloride for 2 hours. Afterward ._ the reaction mixture is used to remove excess Thionyl chloride distilled. 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 7nonane-8-carboxylic acid

4,4-Ethylenedioxy-L-proline is used according to Example 1 (e) 3- (Acetylthio) -2- (methylthio) propionic acid chloride implemented. (8S) -7- / ~ 3- (acetylthio) -2-methylthio-1-oxopropyl_7-1,4-dioxo-7-azaspiro / ~ 4.4_7nonane-8-carboxylic acid is obtained.

d) (8S) -7- (3-mercapto-2-methylthio-1-oxopropyl) -1 _t t> -dioxo-7-azaspiro / ~ 4.4 7nonane-8-carboxylic acid

The product from part (c) is treated according to Example 2 with concentrated ammonia. This gives (8S) -7- (3-mercapto-2-methylthio-i-oxopropyl) -1,4-dioxo-7-azaspiro l_ 4. ¹ J_ / nonane-carboxylic acid 8.

Example 24 35

l- (3-mercapto-2-methylthio-1-oxopropyl) -4,4-dimethoxy-

L-proline

030028/0724

a) 1- / ~ 3- (Acethylthio) -2-methylthio-1-oxopropyl 7-4,4-dimethoxy-L-proline

According to example 3 (d) 4,4-dimethoxy-L-proline is used 3- (Acetylthio) -2- (methylthio) propionic acid chloride implemented. 1- / ~ 3- (acetylthio) -2-methylthio-1-oxopropyl-7-4,4-diiaethoxy-L-proline is obtained.

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

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

15 Example 25

(8S) -7- (3-mercapto-1-oxopropyl) -1,4-dioxo-7-azaspiro- / ~ 4.4 7nonane-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 reacted with S-acetylthiopropionyl chloride according to Example 1 (e). (8S) -7- ] _ 3- (acetylthio) -1-oxopropyl_7-1,4-dioxo-7-azaspiro_ / ~ 4.4_7-nonane-8-carboxylic acid is obtained.

b) (8S) -7- (3-mercapto-1-oxopropyl) -T _> 4-dioxo-7-azaspiro · /~4.4 7nonane-8-carboxylic acid

The product of part (a) is according to Example 2 with concentrated Hydrolyzed ammonia. (8S) -7- (3-mercapto-1-oxopropyl is obtained ) -1, 4-dioxo-7-azaspiro _ / ^ 4.4_ / nonane-8-carboxylic acid.

Example 1 26

1- (3-mercapto-1-oxopropyl) -4,4-dimethoxy-L-proline 35 a) 1- / ~ 3- (acetylthio) -1-oxopropyl 7-4,4-dimethoxy-L-proline

4,4-Dimethoxy-L-proline is used according to Example 3 (d)

^L 030028/0724

Γ "1

^ S-acetylthiopropionyl chloride implemented. 1-] _ 3- (Acetylthio) -1-oxopropyl_7-4,4-dimethoxy-L-proline is obtained.

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

The product of part (a) is according to Example 4 with concentrated Hydrolyzed ammonia. 1- (3-Mercapto-1-oxopropyl) -4,4-dimethoxy-L-proline is obtained.

Example 27

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

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

t5 4,4-Ethylenedioxy-L-proline is used according to Example 1 (e) with 4-acetylthiobutyroyl chloride implemented. One obtains 8 (S) -7- _ / ~ 4- (Acetylthio) -1-oxobutyl_7-1,4-dioxo-7-azaspiro ^ ~ 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 according to Example 2 with concentrated Hydrolyzed ammonia. (8S) -7- (4-mercapto-1-oxobutyl) -1,4-dioxo-7-azaspiro ^ ~~ 4.4_7nonan-

25 8-carboxylic acid.

Example 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; ^ ird according to Example 3 (d) with 4-acetylthiobutyroyl chloride implemented. 1-_ / ~ 4- (Acetylthio) -1-oxobutyl_7-4,4-dimethoxy-L-proline is obtained.

b) 1- (4-mercapto-1-oxobutyl) -4,4-dimethoxy-L-proline

^l *

The product of part (a) is according to Example 4 with con-

030028/0724

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

Example 29

(8S) -7- (2-mercapto-1-oxoethyl) -1, 4-dioxo-7-azaspiro- / ~ 4.4 7nonane-8-carboxylic acid

a) (8S) -7- / ~ 2- (acetylthio) -1-oxoethyl 7-1, U-dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid

4,4-Ethylenedioxy-L-proline is reacted according to Example 1 (e) with ¹⁰ % acetylthioacetyl chloride. One obtains (8S) -7-

/~2-(acetylthio)-1-oxoäthyl_7-1,4-dioxo-7-azaspiro/~4.4_7-nonan-8-carboxylic 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 according to Example 2 with concentrated Hydrolyzed ammonia. (8S) -7- (2-mercapto-1-oxoethyl) -1,4-dioxo-7-azaspiro_ / ~ 4.4_ / nonane-8- _- carboxylic acid.

Example 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 with acetylthioacetyl chloride according to Example 3 (d). 1-J_ 2- (acetylthio) -1-oxoäthyl_7-4,4-dimethoxy-L-proline is obtained.

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

The product of part (a) is just Example 4 with concentrated Hydrolyzed ammonia. 1- (2-Mercapto-1-oxoethyl) -4,4-dimethoxy-L-proline is obtained.

030028 / 072A

Example 31

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

a) (8S) -7- / ~ 3- (acetylthio) -2 _t 2-dimethyl-1-oxopropyl 7-1,4-dioxo-7-azaspiro / 4.4 / nonane-8-carboxylic acid

4,4-Ethylenedioxy-L-proline is according to Example 1 Ce) with 3-acetylthio-2,2-dimethylpropionyl chloride implemented. (8S) -7- / ~ 3- (acetylthio) -2,2-dimethyl-1-oxopropyl_7-1,4-dioxo-7-azaspiro_ / ~ 4.4_7nonane-8-carboxylic acid is obtained.

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. (8S) -7- (3-mercapto-2,2-dimethyl-1-oxopropyl is obtained ) -1, 4-dioxo-7-azaspiro_ £ 4.4 _ / - nonane-8-carboxylic acid.

Example 32

1- (3-mercapto-2,2-dimethyl-1-oxopropyl) -4 _t 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 used according to Example 3 (d) 3-acetylthio-2,2-dimethylpropionyl chloride implemented. 1 -_ / ~ 3- (acetyl thio) -2,2-dimethyl-1-oxopropyl-7-4,4-dimethoxy-L-proline is obtained.

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

L-proline

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

030028/0724

"I _ 68 _

Example 33

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

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

4,4-Ethylenedioxy-L-proline is used according to Example 1 (e) D-3-acetylthio-2-ethylpropionyl chloride implemented. One obtains _ / ~ 7 (S), 8S_7-7W ~ 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 7nonane-8-carboxylic acid

The product of part (a) is hydrolyzed according to Example 2 with concentrated ammonia. You get J_ 7 (S), 8S _ / -

7- (3-Mercapto-2-ethyl-1-oxopropyl) -1, 4-dioxo-7-azaspiro-Z 4.4_ / nonane-8-carboxylic acid.

Example 34

(S) -1- (3-MerGapto-2-ethyl-1-oxopropyl-4,4-dimethoxy-L- 20 proline

a) (S) -1- / ~ 3- (Acetylthio) -2-ethyl-1-oxopropyl 7-4,4-dimethoxy-L-proline

4,4-Dimethoxy-L-proline is reacted according to Example 3 (d) with D-3-acetylthio-2-ethylpropionyl chloride. There is obtained (S) -1 -_ / ~ 3- (acetyl thio) -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 according to Example 4 with concentrated Hydrolyzed ammonia. (S) -1- (3-Mercapto-2-ethyl-1-oxopropyl) -4,4-dimethoxy-L-proline is obtained.

^L 030028 / 072A ^J.

¹ example 35

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

a) 3- / ~ / ~ (4-Methoxy) -phenylmethyl 7-thio 7-2-trifluoromethylpropionyl chloride

A neat mixture of 3.9 g of 1-trifluoromethylacrylic acid and 4.3 g of 4-methoxybenzylthiol are stirred at 100 to 110 ° C. for 1 hour. The mixture is then left cool to room temperature. The solid is recrystallized from cyclohexane. 3 -_ / ~ 7 ~~ (4-methoxy) -phenylmethyl_ / - thio__ / - 2-trifluoromethylpropionylic acid is obtained from 72 to 74 ° C.

._ Treatment of this acid with thionyl chloride gives

15th

3 -] _] _ (4-methoxy) phenylmethyl _ / - thio _ / - 2-trifluoromethylpropionyl chloride.

b) / ~ 8S 7-7- / ~ 3- / ~ / ~ (4-methoxy) -phenylmethyl ethio 7 -2-trifluoromethyl-1-oxopropyl / -7-aza-1,4-dithiaspiro-

/~4.4 / nonane-8-carbonic acid

The 3- / _ ~ 7 ~ (4-methoxy) -phenylmethyl_7-thio_7-2-trifluoromethylpropionyl chloride of part (a) is reacted according to Example 9 (d) with 4,4-ethylenedithio-L-proline. You get _ / ~ "8S_7-7-i ~ 3- / ~ / ~ (4-methoxy) -phenylmethyl_7-thio_7- -2-trifluoromethyl-1-oxopropyl_7-7-aza-1,4-dithiaspiro_ / 4 "._ 4_7-nonane-8-carboxylic acid.

ρ ropyl) -7-aza-1,4-dithiaspiro / 4.4 / nonane-8-carbon- , acid

The product of part (b) is trifluoroacetic acid under nitrogen and anisole mixed. After removal of the solvents under reduced pressure, as is obtained Residue _ / ~ 8S__7-7- (3-mercapto-2- tr if luormethyl-1 -oxo-

35 _

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

J 030028/0724

Γ Π

- 7Ο -

1 example 36

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

a) 3- / ~ 7 ~ (4-methoxy) -phenylmethyl T-thio 7-2-methylthiopropionyl chloride

3W ~ / ~ (4-methoxy) -phenylmethyl_7-thio_7-2-methylthiopropanoic acid, which is produced according to Example 10 of US Pat. No. 4,116,962 is treated with thionyl chloride. Man receives 3- / ~ / ~~ (4-methoxy) -phenylmethyl 7-thio 7-2-methyl- ~ * ~

thiopropionyl chloride.

b) / ~ 8S 7-7- / ~ 3- / ~ / ~ (4-methoxy) -phenylmethyl 7-thio 7-2-methylthio-1-oxopropyl 7-7-aza-1,4-dithiaspiro / ~ 4.4 7-

nonane-8-carboxylic acid
15th

3 -_ / ~ / ~ (4-methoxy) -phenylmethyl_7-thio_7-2-raethylthiopropionyl chloride from part (a) is reacted with 4,4-ethylenedithio-L-proline according to example 9 (d). One obtains / ~ "8S_7- 7-Γ ~ 3- / ~ / ~ (4-methoxy) -phenylmethyl_7-thio_7-2-methylthio-1 -oxopropyl_7-7-aza-1,4-dithiaspiro_ / ~ 4.4_7nonane-8 -carboxylic acid.

c) / ~ 8S 7-7- (3-mercapto-2-methylthio-1-oxopropyl) -7-aza-1.4-dithiaspiro / 4.4 / nonane-8-carboxylic acid The product of part (b) is treated with trifluoroacetic acid under nitrogen and anisole mixed. After removing the solvent under reduced pressure, the residue obtained is _ / ~ 8S_7-7- (3-mercapto-2-methylthio-1-oxo-propyl) -

7-aza-1,4-dithiaspiro / ~~ 4.4 7nonane-8-carboxylic acid. 30 ~

Example 37

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

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

ZlT -

1 ^ -dioxo ^ -azaspiro / 4.4 / nonane-8-carbonic acid

030028/0724

Γ Π

4,4-Ethylenedioxy-L-proline is reacted according to Example 1 (e) with DS-acetylthio-S-methylpropionyl chloride. One obtains ri (S) , 8S ^ 7-7- / ~ 3- (acetylthio) -3-methyl-1-oxopropyl_7_

1,4-dioxo-7-azaspiro / ~ 4.4_7nonane-8-carboxylic acid. 5

b) / ~ 7 (S) _t 8S 7-7- (3-mercapto-3-methyl-1-oxopropyl) -1,4-

dioxo-7-azaspiro / ~ 4.4 7nonane-8-carboxylic acid The product from part (a) is hydrolyzed according to example 2 with concentrated ammonia. One obtains ΓΊ (S), 8S_7-7- (3-mercapto-3-methyl-1-oxopropyl) -1, 4-dioxo-7-azaspiro- _λ ~ 4.4_7nonane-8-carboxylic acid.

Example 38

(S) -1- (3-mercapto-3-methyl-1-oxopropyl) -4 _t 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-3-acetylthio-3-methylpropionyl chloride. There is obtained (S) -W ~ 3- ^{Acet y ^lthio) -3-methyl-1-oxopropyl_7-4,4-dimethoxy-L-proline.

b) (S) -1- (3-mercapto-3-methyl-1-oxopropyl) -4,4-dimeth-

__ oxy-L-proline

Zo *

The product of part (a) is according to Example 4 with concentrated Hydrolyzed ammonia. (S) -1- (3-mercapto-3-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline is obtained.

30 Example 39

1- (3-mercapto-1-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 with 20 ml of hydrogen bromide in acetic acid (30 to 32 Pro-35

cent) offset. The mixture is within 8 minutes

030028/0724

frequently stirred up. Then (the foaming has ended) the yellow-orange solution is covered with a layer of 25 ml of diethyl ether. The rubbery product is triturated. The diethyl ether is discarded. The sticky solid obtained is triturated with fresh diethyl ether and finally with 50 ml of acetonitrile. 2.7 g (85 percent of theory) of 4-keto-L-proline hydrobromide are obtained as a crystalline solid with a melting point of 153 to 155 ° C. (decomposition).
CdLJ ^ - -49 ° (c = 1%; water).
10

b) 1- / ~ 3- (acetylthio-1-oxopropyl 7-4-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 to 5 ° C. while stirring

and by adding solid sodium car-15 in portions

bonat (foaming is kept under control by adding a few drops of diethyl ether) to the pH value
8.0, which requires about 2 g. A solution is then obtained with continued stirring and cooling

of 3i5 g (0.012 mol) of 3-acetylthiopropanoyl chloride in 20th

5 ml of ethyl acetate are added in portions with a pipette, the pH being kept in the range from 7.0 to 8.0 by adding a 25 percent (w / v) sodium carbonate solution (about 10 ml) dropwise
will. After about 10 minutes the pH stabilizes in the range from 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 each time, covered with 50 ml of ethyl acetate, stirred, cooled, carefully

"Adjusted to pH 2.0 with concentrated hydrochloric acid

acidified and saturated with sodium chloride. After the phases have been separated, the aqueous phase is extracted 3 times with 50 ml of additional ethyl acetate each time. The combined organic phases are dried _{over MgSO 1.} The Lö _ec solvents is evaporated to give at the end of a
Pressure of 0.2 torr results. M, 8 g of a yellow-

030028/0724

orange glass-like residue. This residue is dissolved in 35 ml of ethyl acetate and treated with a solution of 3.5 g of dicyclohexylamine in 5 ml of ethyl acetate. After inoculation and trituration, crystalline 1- / ~ 3- (acetylthio-1-oxopropyl) -7-4-oxo-L-proline dicyclohexylamine salt precipitates. After standing overnight, 2.7 g of an almost colorless product with a melting point of 191 ° to 193 ° C. (decomp.) Are obtained.
Γθ <_7 p ⁶ = -24 ° (c = 1%; CHCl ₃ ).

This dicyclohexylamine salt is according to Example 1 (e) converted into the free acid using potassium hydrogen sulfate. 3.7 g of 1 -_ / ~ 3- (acetylthio) -1-oxopropyl-7-4-oxo-L-proline are obtained as a pale yellow glassy solid.

c) 1- / ~ 3- | acetylthio) -1-oxopropyl 7-4, 4-dimethylthio-L - proline

1 -_ / ~ 3- (Acetyl thio) - 1-oxopropyl_A4-oxo-L-proline is according to Example 9 (a) reacted with methyl thiol. 1 -_ / _ "~ 3- (acetylthio) -1-oxopropyl-7-4,4-dimethylthio-L-proline is obtained.

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

^ The product of part (a) is according to Example 2 with concentrated Hydrolyzed ammonia. 1- (3-Mercapto-1-oxopropyl) -4,4-dimethylthio-L-proline is obtained.

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 7decane-3-

carboxylic acid

030028 / 072A

1 According to Example 1, using 2.2-

Diethyl 1,3-propanediol instead of ethylene glycol in part (c) / ~ 2 (S), 3S_7-2-jT'3- {acetylthio) -2-methyl-1-oxopropyl_7-8,8-dimethyl-6,10-dioxo-2-azaspiro ^ 4.5_7decane-3-carbon-

5 acid.

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

8,8-dimethyl-6,10-dioxo-2-azaspiro / ~ 4.5 7decane-3-car-

boric acid

The product of part (a) is according to Example 2 with concentrated Hydrolyzed ammonia. One obtains j ^ ~ 2 (S), 3S_7-2- (3-mercapto-2-methyl-1-oxopropyl) -8,8-dimethyl-6,10-dioxo-2-azaspiro _ / ^ 4.5_ / decane-8-carboxylic acid.

Example 41

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

7-azaspiro / ~ 4.4 7nonane-2-methyl-8-carboxylic acid

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

^ methyl ester 20 *

A mixture of 8 g (0.025 mol) of N-carbobenzyloxy-4,4-dimethoxy-L-proline methyl ester from Example 3 (a), 2.4 g (0.032 mole) 1,2-propanediol, 0.4 g p-toluenesulfonic acid monohydrate and 400 ml of toluene is heated to reflux temperature (110 to 112 ° C). The amount of reflux is set so that that the solvent slowly distilled into a graduated cylinder using a Dean-Stark tube. After 80 ml of solvent have been collected, the same volume of fresh solvent is poured into a dropping funnel added to the reaction flask. This process (removal and replacing 80 ml of solvent) repeated 4 times.

The mixture is then left to stand overnight and then washed twice with 100 ml of water each time. The United

030028/0724

Wash liquids are extracted with 100 ml of toluene. The combined organic phases are over MgSO ₁ . dried. The solvent is removed on a rotary evaporator, the final pressure being 0.2 torr. 8.2 g (99 percent of theory) of N-carbobenzyloxy-4,4- (1-methylethylenedioxy) -L-proline methyl ether are obtained 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 from part (a) are dissolved in 80 ml of methanol. The solution will be at -1 to 4 ° C dropwise with 18 ml (0.036 mol) 2 η sodium hydroxide solution offset. The mixture is then 1 hour

at 0 ^° C. and then overnight at room temperature

permit. After removing about half of the solvent on a rotary evaporator, the solution is 150 ml Diluted water, washed with 100 ml of diethyl ether (the washing liquid is discarded), while cooling with 6.3 ml

Hydrochloric acid (1: 1) acidified to pH 2 and 4 times 20th

extracted with 75 ml of ethyl acetate each time. The combined extracts are washed with 50 ml of saturated sodium chloride solution and dried over MgSO ₂ . dried. After evaporation of the solvent, 8 g of a red-orange color are obtained

__ viscous oil. This oil is dissolved in 50 ml of acetonitrile. 25th

The solution is heated with stirring and with 3.8 g of 1-adamantanamine offset. The corresponding salt precipitates quickly. After overnight cooling, the material is filtered off, Washed with cold acetonitrile and with diethyl ether and "dried under reduced pressure. 10.3 g are obtained

crude adamantanamine salt from F. 202 to 20 ¹ IC (dec.). Λ 7p ⁶ = -13 ° (c = 1%; methanol).

After trituration with 50 ml of boiling acetonitrile and then Cooling gives 9.4 g of a pale yellow

brown salt from m.p. 202 to 20U ⁰ C (decomp.).

/ o (/ * ^b = - 13 ° (c = 1%; methanol)

030028/0724

The above adamantanamine salt is suspended in 40 ml of ethyl acetate. The suspension is treated with 1 η hydrochloric acid while stirring. After 2 clear phases have formed, these are separated. The aqueous phase is extracted 3 times with 40 ml of additional ethyl acetate each time. The combined organic phases are dried _{over MgSO 1.} The solvent is evaporated, the final pressure being 0.2 torr at 40 °. 5.8 g (72 percent of theory) of N-carbobenzyloxy-4,4- (1-methylethylenedioxy) -L-proline are obtained 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- (1-methylethylenedioxy) -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 atm. The catalyst is filtered off under nitrogen and washed with methanol. The united FiI-20

Trät are evaporated, whereby the pressure at the end 0.1 to 0.2 Torr. The crystalline residue obtained is suspended in 200 ml of methanol. The one after repeating the residue obtained by evaporation is under diethyl ether rubbed. It is then evaporated again. 3.0 g (94 percent of theory) of 4,4- (1-methylethylenedioxy) -L-proline are obtained as a pale yellow-brown solid from F.

219 to 2 sintering).

219 to 221 ° C (dec .; previously gradual darkening and

CuJ ^ = -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 7nonane-2-methyl-8 -carboxylic acid

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

030028/0724

reacted thio-2-methylpropionyl chloride in 40 ml of water. 5.0 g of a viscous yellow product are obtained. This. The product is treated with 2.8 g of dicyclohexylamine in 45 ml of ethyl acetate. 4.2 g / ~ 7 (S), 8S_7- 7-J_ 3- (acetylthio) -2-methyl-1-oxopropyl_ / - 1,4-dioxo-7-azaspiro_ / ~ 4.4_7nonane-2-methyl are obtained -8-carboxylic acid dicyclohexylamine salt in the form of an almost colorless solid with a melting point of 170 to 172 ° C (sintering 168 ° C).

/ "I * Jl ⁵ = -58 ° (c = 1%; ethanol).

10 - -

After crystallization from 12 ml of acetonitrile, 3.85 g (51 percent of theory) of a colorless salt with a melting point of 170 ° to 172 ° C. are obtained

(Sintering 168 ° C).

Λ ~ (Χ_7ρ ⁵ = -57 ° (c = 1%; ethanol).

¹ SC _{1X (} H ₂₁ NO ₆ S. C ₁₂ H ₂₃ M CHNS

calc .: 60.90 8.65 5.46 6.26 found: 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 with 45 ml of 10 percent potassium hydrogen sulfate solution while stirring. The 2 phases obtained are separated. The aqueous phase is extracted 4 times with 40 ml of ethyl acetate. The organic phases are combined and dried over MgSO ^. After evaporation of the solvent, 2.5 g (51 percent of theory) of jT "7 (S), 8S_7-7 -_ / ~ 3- (acetylthio) -2-methyl-1-oxopropyl_7-1,4 are obtained dioxo-7-azaspiro ^ 4.4_ / nonan-2-methyl-8-carboxylic acid as a colorless solid, melting at 65 to 68 ⁰ 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 according to Example 2 with con-

030028/0724

hydrolyzed centered ammonia. 2.05 g of l_ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro ^ ~ 4.4_7nonane-2-methyl-8- carboxylic acid as a viscous colorless oil.

5, -τ

■ 25 D

= -57 (c = 1%; ethanol).

Examples 42 to 75

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

Column I.

HC ³ O

CH.

O -

< ^H 2 ^C) p Cbz-N -

C-COOH

Column II

X.

Column III

^R 9 . ^R 10 \ '

Cbz-N

(CH ₂ ) _q

C-COOH

Column IV OR ₁ R, O

II I ⁴ i ³ H

R ₈ -CS- (CH) _1n -CC-Cl

030028/0724

30th 35

Column V

R _B R ₁ ,

10

/ ^C

OR ₄ R ₃ O < ^H 2fp «* 2>,

II ι ⁴ ι ³ Ii II

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

i I

R.
^R 6

^R 9 Λθ

Column VI

25th

HS- (CH) -C -C -C -C -COOH

030028/072

Example p

^R 3 ^R 6

R ₄ .

42

CaJ O O ISJ OO

43

HC-C , CH CH 3 II / ² I i ^v
O O H H CH ₃ H C ^{3 N} c CH CH, S. / 3 3 H H S. H

CH.

cn.

44 .CH OH HC CH

* 1

0 H

CU.

CII.

CO -fcH-

10

15th 20th

Β— (!)

B-O

IF

ο χ

W.
CM
U CJ
χ CM
/ δ-ο X Oil CM X \ '
\ CJ-O X
Ι ϋ -
I. X ϋ -O
CM X I.
χ ™ I.
ο -
J (M ■ OT ■ OT

CO

»Τ

030028/0724

(OJ δ

■ η

C. CN

■ Η

ιη

X S U - O S

C - to

I I

X X

<Ν

fM X

U-OS V

S U - O S

U-OS CS

ο «η

030028/0724

[ο

CJ

S O -O S

cn in

CJ

B CJ -CO S

δ -ο β

-O *

in m

U-CO B

«Ν /

CJ

cn a

030028/0724

δ (θ)

Tin

S-O B ύ-ΟΧ

-Γ ¹

S - o κ

in the

SO

ο-οχ

00 in

in

030028/0724

Ö -W B 0-δ

O - «B O -S «Ν Γ4

B B

2nd-8th

CM

ϋ -

CN

U]

CO

ϋ -δ

ο «ο

VO

CN

νθ

VO

030028/0724

"et

10

«Μ ■

15th

δ -S

υ -5

6 -

ο —ο

CM

Γ.Φ

B-S

δ-δ

ο - ο

δ δ-δ

ο υ - δ

(M

M «Ο

«Ο« Ο

Γ »

«Ο

VO

10

030028/072 /,

- 87 -

2S51200

«Η

ta

■ τ *

"Vm

δ-δ

r X

δ-§

υ-g

«Μ ^W

ρ

δ

α -5 γ *

<Ν

δ - §

-δ

(M

Γ *

030028/0724

1 example 75 to 124

According to Example 41, the disubstituted compounds of column I (or their alkyl esters) with a molar equivalent of the alcohol or thiol of column II. The compound of column III is obtained. Another possibility is the dimethoxy substituted compound from column I (or their alkyl esters) with a molar excess of the alcohol or thiol from column II to treat, whereby one obtains the disubstituted compound of column IV. After removing 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 from column V gives the products from column VI or VII. These compounds can then be added to the products the column VIII or IX are hydrolyzed.

Column I Column II

20 fl * 1

^X 1 ^X 1 R ₂ -XH

(H. C) (CH.)

^Δ \ ^ρ ι ^q

25 I

CbZ-N C-COOH

0 3 C 0 2 8/0 7 2

Column III Column IV

χ, χ «

^(H 2f'p

Cbz-N

C-COOH ι

Cbz-N

ι ^{2 q} .

C-COOH H

Column V

0 R ₁ R-

1 I ⁴ I ³ II R ₀ -CS- (CH) -C - C-Cl

I R,

, Column VI

O R. R.

Il I ⁴ ι ³ Il

R ₈ -CS- (CH) _1n -CC

N -

C-COOH

030028/0724

- 9Ο -

Column VII

2S51200

Il

Il

R ₈ -CS- (CH) _1n -C- C-

2T ¹ P

(CH ₂ ) _q

Column VII I

0 (H C) 2

, 4, 3 "

HS- (CH) -C-C m

C) 2, ρ

(CH)

, 2 q C-COOH

030028 / 072A

Column IX

HS- (CH)

R.

ι H

C-C

«" Λ C-COOH

030028/0724

δ "

e ι *

SS

ΓΟ

S S

«Ν

■ η
Γ » <H r-t
• S «0 i
1

a \

ΟΟ

Γ »

io]

¹ cl

C *

Γ

Ο CO

030028/0724

2S512G0

ι:

OT

CM Oil

ο »

Oil

Oil

T I

ro

cn

PI

<Μ

δ 6

ΙΛ

ro

cn

ΓΙ

VO

ro

ίΜ

Oil

δ f

030028/0724

29512G0

& ff »- f (b f &<

οι

00

ιη

ns j

ι ι ι

δ 6

ö a

ιη

CJ

Il

δ δ

δ "?

c> i η ^ in \ o C * co

01 0t OI O ^ O O ^ O ^

030028/0724

δ δ

[oil

! / ■

CQ

(ρ /

(M

ιη

? Φ

(Q I.

ι-: • π

(Q I

ιη

(M

(M

(D

CSl

030028/0724

• «Μ

δ [ο.

γ-Ί

SIS δ δ

«Η <η η χ

C *

<Ν

BSB B B S S £

η »η 5

in ^S.

[Ol «^

<N

O) -I Γ4

fM (Μ

δ δ δ

(N (N

(N

ιη νο

030028/0724

to

§ Γ

(Oi ^

m co

S. υ CJ ι I.

U O

CM

cm i *>

ω σ>

δ δ

ο r-4 CM ΓΟ CN CM CM CN r-l .- » r-l

030028/0724

1 example 125

(S, S _t S _t S) -7.7 ^t - / ~ Dithiobis- (2-methyl-1-oxo-3,1-propanediyl) 7-bis- / 1, M-dioxa-7-azaspiro / 4.4 Tnonane-S-carboxylic acid

3.0 g (0.0109 mol) _ / 77 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1, 4-dioxo-7-azaspiro_ £ 4.4_ / nonane-8-carboxylic acid from Example 2 are dissolved in 80 ml of water. The pH the solution is adjusted to 6.5 with 1 η sodium hydroxide solution. This solution is added dropwise with stirring a total of 11 ml of 0.5 M iodine solution in 95 percent ethanol (6.34 g of iodine / 50 ml of solution) are added, the pH value through Addition of 1 η sodium hydroxide solution is kept in the range from 5.5 to 6.5. After 15 minutes there will be traces of excess iodine by adding dilute sodium thio-

sulfate solution eliminated. The solution is made to about 50 ml a-15

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

30 ml of methylene chloride are then added. The mixture is saturated with sodium chloride and stirred. After this The aqueous phase is separated 3 times with 20

ml of additional methylene chloride extracted. The united 20

organic phases are over MgSOj. dried. Then

the solvent is evaporated, the pressure at the end being 0.2 torr. The brittle residue is under Diethyl ether rubbed. After evaporation of the diethyl

ether gives 2.8 g of pale yellow solid residue. The-25

This product is redissolved in 50 ml of methylene chloride and washed 3 times with 10 ml of water each time. The combined aqueous phases are extracted with 20 ml of methylene chloride. The combined organic phases are dried _{over MgSO 1.} After evaporation and trituration with diethyl ether, 2.2 g (73 percent of theory) (S, S, S, S) -7,7'-r ~ dithiobis- (2-methyl-1-oxo-3, 1-propanediyl) _7bis Γ ~ λ , 4-dioxo-7-azaspiro_ £ 4.4_7nonane-8-carboxylic acid as a cream-colored amorphous solid with a melting point of 61 to 63 ° C (foaming; sintering

35 ⁵ ° ^C 1 *

/ OiJi ₁ ⁶ = -.92 ° (c = 1%; ethanol)

030028/0724

- C. 99 - 6th H 4, N 11 S. 2 Q b 1 200 H ₂ O 46 6th , 05 94 10 , 31 ber .: 46 , 63 , 29 63 , 96 - found: , 52

5 Example 126

(S, S, S, S) -7.7 ^t - / ~ Dithiobi3- (2-methyl-oxo-3,1-propanediyl) 7-bis- / ~ 7-aza-1,4-dithiaspiro / ~ 4.4 ~ nonane-8-carboxylic acid

£ ~ 7 (S), 8s_7-7- (3-mercapto-2-methyl-1-oxopropyl) -7-aza-1,4-dithiaspiro_ / ~ 4.4_7nonane-8-carboxylic acid from Example 10 is mixed according to Example 125 with Iodine implemented. (S, S, SS) -7,7 '-./"* dithiobis- (2-methyl-1-oxo-3,1-propanediyl_) 7-bis- _ / ~ 7-aza-1,4 are obtained -di thiaspiro_ / ~ 4.4_7nonane-8-carboxylic acid.

15 example ^?

(S, S _t S, S) -1,1 '- / ~ Dithiobis- (2-methyl-1-oxo-3,1-propanediyl) bis- / 4,4-dimethoxy-L-proline /

(S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline Example 4 is reacted with iodine according to Example 125. (S, S, S, S) -1,1 '- / ~ dithiobis-£ -methyl-1 is obtained -oxo-3,1-propanediyl) _7-bisi-jT ~ 4,4-dimethoxy-L-proline_7.

Example 128

/ ~ 7 (S) _t 8 (S) 7-7- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl 7-1i4-dioxo-7-azaspiro / ~ 4.4 7nonane-8-carboxylic acid methyl ester

A solution of the product from Example 1 in diethyl ether is treated with a slight excess of diazomethane. After 2 hours of standing at room temperature, the solvent is evaporated ^. One obtains / ~ 7 (S), 8S 7-7- / ~ 3- (acetyl thio) -2-methyl-1-oxopropyl _ / - 1,4-dioxo-7-azaspiro- ^ ~ 4.4__7nonane-8-carboxylic acid methyl ester.

Example 129

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

030028/0724

2S51ZQQ

The product from Example 128 is hydrolyzed according to Example 2 with concentrated ammonia. One obtains / ~~ 7 (S), 8S_J7-7_ (3_Mercapto-2-methyl-1-oxopropyl) -1, H-dioxo-7-azaspiro r ~ k . iJ ^ Tnonane-S-carboxylic acid methyl ester.

Example 130

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

A solution of the product from Example 3 in diethyl ether

is treated with a small excess of diazomethane. After standing at room temperature, the solvent becomes evaporated. (S) -I- / ~ 3- (acetylthio) -2-methyl-1-oxopropyl-7-4,4-dimethoxy-L-proliln-methyl ester is obtained.

Example 131

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

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

Example 132

Sodium salt of / ~ 7 (S), 8S 7-7- (3-mercapto-2-methyl-1-oxopropyl) -1, U-dioxo-7-azaspiro / ~~ 4.4 7nonane-8-carboxylic acid

A solution of 1.0 g of the product from Example 2 is dissolved in 10 ml of water. The solution is made with 1 equivalent of sodium hydrogen carbonate treated. After freeze drying the

30 - -

Solution one obtains the sodium salt of j_ 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

hydrogen carbonate the corresponding potassium salt.

030028/0724

"2S512OO

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

Similarly, using potassium

hydrogen carbonate the corresponding potassium salt.

Example 134

There are 1000 tablets of the composition given below manufactured:

2. "" 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1, 4-dioxo-7-azaspiro ^ ~~ 4.4_7nonane-8-carboxylic acid 100 mg

Corn starch 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 mixed. The mixture is dried

net and grind to a fine powder. The microcrystalline cellulose and the magnesium stearate are then mixed in with granulation. The mixture is then
compressed in a tablet press to 1000 tablets with an active ingredient content of 100 mg each.

030028/0724

¹ example 135

According to example 134 tablets with a content of per 100 mg (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-

dimethoxy-L-proline produced.
5

Example 136

1000 tablets with a content of 50 mg _ / ~ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro are made from the following ingredients - J_ 4.4_ / nonane-8-carboxylic acid produced.

X ~ 7 (S) _f 8S_7-7- (3-mercapto-

2-methy.l-1-oxopropyl) -1, 4-

dioxo-7-azaspiro _ / ^ 4.4 _ / - 15 nonane-8 _r carboxylic acid 50 g

Lactose 100 g

microcrystalline

Cellulose (Avicel) 150 g

Corn starch 50 g

²⁰ magnesium stearate 5 g

Active ingredient, lactose and microcrystalline cellulose are mixed and then mixed with the corn starch. The magnesium stearate is then added. The dry mixture becomes 1000 tablets weighing each 355 mg and an active ingredient content of 50 mg. The tablets are made with a methyl cellulose solution (Methocel E 15), which contains dye containing yellow no. 6, coated.

Example 137

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

030028/0724

235

Example 138

Two-piece No. 1 gelatin capsules each come with a Mixture of the ingredients listed below :

Sodium salt of / "7 (S), 8S_7-

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

propyl) -1, ^ - dioxo-T-azaspiro-

100 mg 7th mg 193 mg

Magnesium stearate

Lactose

Example 139

According to Example I38, gelatin capsules are made with a content to 100 mg each of the sodium salt of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline manufactured.

example
The ingredients listed below become one

Solution for injection prepared: 20

Γ7 (S) , 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1, k dioxo-7-azaspiro ^ ~ 4.4_7-nonane-8-carboxylic acid 500 g

4-hydroxybenzoic acid

methyl ester 5 g

4-hydroxybenzoic acid

propyl ester 1 g

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 to a volume of Brought 5 liters. The solution is filtered through a sterile filter and aseptically placed in pre-sterilized bottles.

L - 030028/0724

^Γ - 104 -

brought them with pre-sterilized rubber closures
be locked. The vials each contain 5 ml injection solution with an active ingredient concentration of 100 mg / ml.
5

Example 141

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

Example 142

6000 tablets, each containing the following ingredients, are produced:

/ ~ 7 (S), 8S_7-7- (3-mercapto-2-methyl-15 1-oxopropyl) -1,4-dioxo-7-azaspiro-

_ / ~ 4.4_7nonane-8-carboxylic acid 100 mg

Microcrystalline cellulose

(Avicel) 100 mg

Hydrochlorothiazide 12.5 mg

Lactose (U.S. Pharmacopeia) 113 mg

Corn starch (U.S. Pharmacopeia) 17.5 mg

Stearic Acid (U.S. Pharmacopeia) 7 mg

350 mg

The appropriate amounts of active ingredient, Avicel and a

Part of the stearic acid are mixed. The coarse ingredients are ground and passed through a No. 2 sieve. Afterward be hydrochlorothiazide, lactose, corn starch

and the remaining stearic acid mixed in. The mixture becomes 30

in a tablet press to capsule-shaped tablets of

each pressed 350 mg weight. The tablets are grooved so that they can be cut in half.

030028/0724

Example 143

According to example 142 tablets with a content of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline and hydrochlorothiazide.

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

030028/0724

Claims (1)

VOSSIUS VOSSIUS TAUCHNEH! -JEUNEMANN- RAUH PATENT LAWYERS _Ä ----- SIEBERTSTRASSE A ■ 8OOO MUNICH 88 · PHONE: (Ο8Θ) 47 4O75 CABLE: BENZOLPATENT MÖNCHEN · TELEX 5-39 453 VOPAT D 5 ET: P Case: M-972 314-S E.R. SQUIBB & SONS, INC. "Ketal and thioketal derivatives of mercaptoacylprolines and -pipecolic acids. Processes for their preparation and their Use to treat high pressure Priority: December 22, 1978, V.St.A., No. 972 314 15th Claims 1. Ketal and thioketal derivatives of mercaptoacylprolines - ^ and- pipecolic acids of the general formula I. R ₄ R, 0 (HC) (CH) 30, <, 3 _N 2 ₍ ρ ₍ 2 q R ₅ -S- (CH) -C -CN C-COOR ^{5 m} ii * S. ^H 030028/0724 in the R denotes 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 - < ^CH 2> n or - (CH ₂ ) or R ₁ and R ₂ together are a polymethylene radical of the general formula mean, 030028/0724 X ^, Χ_ and X, independently of one another , mean oxygen or sulfur atoms , R- and Rj. Independently of one another are hydrogen atoms, lower alkyl, lower alkylthio, - (CHg) _n -SH- or halogen-substituted lower alkyl radicals, Rg denotes a hydrogen atom or a lower alkyl radical, with the proviso that Rg is a lower alkyl radical only if R ₃ also denotes a lower alkyl radical, m has the value 0, 1 or 2, η has the value 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 ₇ ej.n is a hydrogen atom, a C - ^ - alkyl, C ^ -alkoxy, C,! .- alkylthio radical, a chlorine, bromine or fluorine atom, a trifluoromethyl or hydroxyl group, Rq and R _{10 are} both hydrogen atoms, both lower alkyl radicals or one radical thereof is a hydrogen atom and the other radical is a lower alkyl, halogen-substituted lower alkyl or hydroxyl-substituted lower alkyl radical or a radical of the general formulas - ^(CH 2'n 030028/0724 mean, R ₁ . a hydrogen atom , a protective group that can be removed by hydrolysis or by chemical means or, under the preceding ⁵ . suspension that neither R ~ nor R ₁ ^ represent a radical of the general formula - (CHp) _n -SH, a sulfide of the general formula I ⁴ R. R, 0 I ⁴ I ³ H -S- (CH) -C- C m ι (H ₂ Op ^(C Vq C-COOR I * means, as well as salts of these compounds. 2. Compounds according to claim 1, characterized in that ρ has the value 2 and q has the value 1. 3. Compounds according to claim 1, characterized in that ρ has the value 1 and q has the value 2. 4. Compounds according to claim 1, characterized in that ρ and q both have the value 1. 5. Compounds according to claim 4, characterized in that independently of one another oxygen or that X «and Sulfur atoms, R is a hydrogen atom or a lower alkyl radical, R ₁ and R_ are each C _1. -Alkyl radicals or two methylene groups connected to one another, R ₃ and R _{4 are} each hydrogen atoms or C _1. -Alkyl radicals, R _{5 is} a hydrogen atom, a C _{1. -Alkanoyl} - Or benzoyl radical and R _ß denotes a hydrogen atom and m has the value O or 1. 030028/0724 6. Compounds according to claim 4, characterized in that X and X _{2 are} each oxygen atoms, R, R ₄ , R ₅ and R, each hydrogen atoms, R, and R_ each C. ₄ alkyl radicals or each methylene groups which complete an ethylenedioxy ring , and R _{3 is} a methyl group and m is 1. 7. Compounds according to claim 4, characterized in that X ₁ -R ₁ and X ₃ -R _{3 complete} an ethylenedioxy ring. 8. Compounds of the general formula f4 f3 f R.-S- (CH) - C C N 1 COOR ⁵ I. ^R 6 20 ^{in the} R denotes a hydrogen atom or a lower alkyl radical, R and R ₂ independently of one another a lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl radical, a radical of the general formulas or R ₁ and R_ together represent a polymethylene radical of the general formula ^R 9/10 030028/0724 form. X ₁ , X_ and X, independently of one another, are oxygen or sulfur atoms,
5 R ₃ and R ₄ independently of one another are hydrogen atoms, lower alkyl, lower alkylthio radicals, radicals of the general formula - (CH ₀ ) -SH or halogen-substituted lower alkyl radicals,
10 R- denotes a hydrogen atom or a lower alkyl radical, with the proviso that R ₆ only denotes a lower alkyl radical if R, is also a lower alkyl radical,
15th m has the value 0, 1 or 2,
η has the value 1, 2 or 3,
t has the value 2 or 3, R _{7 represents} a hydrogen atom, a C _{.. Alkyl, C 1} --alkoxy, C ₁ .- alkylthio radical, a chlorine, bromine or fluorine atom or a trifluoromethyl or hydroxyl group, 25th R_ and R ₁₀ both hydrogen atoms or both lower alkyl radicals or one radical thereof is a hydrogen atom and the other is a lower alkyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl radical, a radical of the formulas - (CHJ- / O 2 η means, or - (GH-) .-fS) Rj. A hydrogen atom, a protective group which can be removed by hydrolysis or by chemical means or, provided that neither R ₃ nor R. is a radical of the general formula - (CH ₀ ) -SH, a radical of the general ^L 030028/0724 means a formula -S- (CH) - C η 9. Compounds according to claim 8, characterized in that R is a hydrogen atom, R ₁ . a hydrogen atom, R_ and R _fi each C ₁ ^ -alkyl radicals or R ₆ a hydrogen atom and R-, a hydrogen atom, a C, ^ -alkyl radical, a trifluoromethyl, methylthio or mercaptomethyl group, R, - a V / water atom , a C w -alkanoyl or benzoyl radical, X ₁ and Xp oxygen or sulfur atoms, R ₁ and Rp C ₁ j-alkyl radicals, radicals of the general formulas or denote, m has the value 0 or 1 and R ₇ denotes a hydrogen, chlorine, bromine or fluorine atom or a methyl, methoxy, methylthio, trifluoromethyl or hydroxyl group. ΙΟ. Compounds according to claim 9, characterized in that R is a hydrogen atom, R ₁ ^ is a hydrogen atom, R_ and R, both methyl groups or R _{fi is} a hydrogen atom and R- is a hydrogen atom, a methyl, trifluoromethyl, methylthio or mercaptomethyl group, R ₅ ^a hydrogen atom, an acetyl or benzoyl group, X. and X ₂ 030028/0724 have the same meaning, R. and R _{2 are} methyl or ethyl groups or radicals of the general formulas R-, or mean, m has the value 0 or 1 and R_ is a hydrogen, Chlorine, bromine or fluorine atom or a methyl, methoxy, methylthio, trifluoromethyl or hydroxyl group means. 11. Compounds according to claim 10, characterized in that R, R _1. , R, - and Rg are hydrogen atoms, R ~ is a methyl group, m is 1 and R. and R_ are both methyl or ethyl groups. 12. Compounds according to claim 11, characterized in that X ₁ and Xp both represent oxygen atoms. 13. (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-di- methoxy-L-proline. 14. (S) -1- (3-Mercapto-2-methyl-1-oxopropyl) -4,4-di-30 ethoxy-L-proline. 15. Compounds according to claim 8, characterized in that R is a hydrogen atom, R ₁ . a hydrogen atom, R_ and Rg both C ₁ "-alkyl radicals or R _t a hydrogen atom and 1-4 ο R-3 is a hydrogen atom, a C ₁ ι, -alkyl radical, a tri- 030028/0724 fluoromethyl, methylthio or mercaptoraethyl group, Rc is a hydrogen atom, a C, ^ -alkanoyl or benzoyl radical, ^X i- ^R i and Xa-R ₂ are linked to form one of the following radicals ^C - ^C \ ^CC \ I ^R io ''<\ I ^R io O O 10 io "| I ^R 10 H ₂ C CH 15 OS I ' \ / ο S / ίο 20 "%, r ^ _" or f > _{2 | |} 2 H ₂ C CH, O O ' Rq and R ..- both hydrogen atoms or both Cj, -alkyl radicals or R _{q is} a hydrogen atom and R _{10 is} a C ₁ ! J-alkyl radical, hydroxyl- _{substituted C 1} ^ -alkyl radical or halogen-substituted C ₁ , -alkyl radical and Bi is the value Has 0 or 1. 16. Compounds according to claim 15, characterized in that Rq and R ₁ - both hydrogen atoms or R _{q is} a hydrogen atom and R _{10 is} a methyl, hydroxymethyl or trifluoromethyl group. 030028/0724 Γ "1 * 17; Compounds according to claim 16, characterized in that R is a hydrogen atom, R ₁ ^ is a hydrogen atom ^ R ₃ and Rg both methyl groups or Rg a hydrogen atom and R- a hydrogen atom, a methyl, trifluoromethyl, 5 methylthio or mercaptomethyl group, R ^ a hydrogen atom, an acetyl or benzoyl group and X ₁ -R ₁ and Xp-Rp to form one of the following remnants are connected ₁₀ H, C - CH ₀ HC CH-CH, 2,, ^{2 2} II ³ HC CH-, H-C-CH-CH Il Il SS S. S / ^CH 2 \ H.C CH HC CH. 20 ² I 1 ^{2 2} I ι ² OO OO \ S or * ^ v > * 25 18. Compounds according to claim 17, characterized in that R, R ₁ ,, R (- and Rg are hydrogen atoms and R- is a methyl group and m is 1. 30 19. j_ 7 (s), 8S _ / - 7- (3-mercapto-2-methyl-1-oxopropyl) -1,4- dioxo-7-azaspiro_ £ 4.4_ / nonane-8-carboxylic acid. 20 .. l_ 2 (S), 3S _ / - 2- (3-mercapto-2-methyl-1-oxopropyl) - 35 - - 6,10-dioxo-2-azaspirq ^ 4.5_ / decane-3-carboxylic acid. 030028/0724 21. f ~ 7 (S) , 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -7-aza-1,4-dithiaspiro_ £ 4.4_ / nonane-8-carboxylic acid. 22. ^ ~~ 7 (S), 8S_7-7- (3-mercapto-2-methyl-1-oxopropyl) -1,4-dioxo-7-azaspiro_ £ 4.4_ / nonane-2-methyl-8-carboxylic acid 23. Compounds according to claim 17, characterized in that mean methyl group and m has the value 1. Hydrogen atoms and R_ a trifluorine 24. (8S) -7- (3-mercapto-2-trifluoromethyl-1-oxopropyl) - 1,4-dioxo-7-azaspiro / ~ ¹ l. ¹ i_ / nonane-8-carboxylic acid. 25. Compounds according to claim 8, characterized in that R_ and R ₁ , no - (CH ₀ ) -SH radical and R _n a radical ^{3 5} the general formula -S— (CH) _- -CC N- (L) -COOR means. 26. (S, S, S, S) -7,7 '-_ / Dithiobis- (2-methyl-1-oxo-3,1- propanediyl) _7-bis -_ / ~ 1, U-dioxo-7-azaspiro / ~ 1.4_7nonane-8-carboxylic acid. 030028 / 072A γ "ι 1 27. Process for the preparation of the compounds according to claim 1, characterized in that one (1) a substituted proline or a substituted pi-5 pecolic acid of the general formula f2 10 <H _{2p q} COOR with an acid of the general formula Ri Rt I I R £ -S- (CH) _1n -C-COOH 20 Smj ^R 6 in which R * is a hydrogen atom or one by hydrolysis or chemically removable protecting group 25 is, couples, or (2) a compound of the general formula _R is (CH) CCNC COOR 5 m * R ^H 35 ^R 6 J 030028/0724 in which R ¹ - has the above meaning with an alcohol or thiol of the general formulas or I ¹ I ' 10 HH implements, whereby a product is obtained in which R _{5 represents} a hydrogen atom or a protective group which can be removed by hydrolysis or chemically, optionally removing the protective group to form a product in which R _{5 represents} a hydrogen atom, and optionally Products in which R _{5 represents} a hydrogen atom, with the formation of a product in which R _{5 represents} a radical of the general formula fi «a hh '" ² ~' ^{p (} "' ² ' -S- (CH) _n -C-CO-N ft-COOR R- oxidized. ⁶ H. J 030028/0724 - ¹⁴ - 295120 ο " ¹ 1 28. Use of the compounds according to claim 1 for treatment of high pressure. 29. Medicines, characterized by a content of min-5 at least one compound according to claim 1 as an active ingredient. 30. Medicament according to claim 29, characterized by an additional content of a diuretic. ^L 030 0 28/0724