DD215539A5 - PROCESS FOR PREPARING NEW SUBSTITUTED PYRROLIDINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel substituted pyrrolidinone derivatives for use as medicaments. The aim of the invention is the provision of new pyrrolidinone derivatives with increased effectiveness with regard to the improvement of the memory performance as well as with a new spectrum of activity including the Antitumoraktivitaet. According to the invention, lactam dipeptides of the formula I or their salts are prepared in which Z is an optionally substituted alkylene radical which together with the amide grouping forms a five-membered ring, R is highly hydrogen, optionally substituted lower alkyl or aryl, X is oxygen or -NR is H 2, where R is high 2 is hydrogen or lower alkyl, R is high hydrogen, optionally substituted lower alkyl or aryl or R is high and R is high together with optionally substituted trimethylene, and the radical -N (R tall 4) -WN (R tall 12) -R high 13 is the radical of a peptide amide having 1-4 amino acids, except those compounds in which Z is trimethylene and at the same time R is highly hydrogen, C 1-4 -alkyl, aryl or aryl-lower alkyl, X is NH, R is high aryl, alkyl or hydrogen, R is high 4, R is high 12 and R is high 13 is hydrogen and W is the radical -CH (R tall 3) -CO-.

Description

Process for the preparation of new substituted pyrrolidinone derivatives _ ^. ,

Field of application of the invention

The invention relates to a process for the preparation of novel substituted pyrrolidinone derivatives with valuable pharmacological, e.g. tumor-inhibiting, properties.

The compounds prepared according to the invention are used as medicaments, in particular for the treatment of cerebral performance insufficiency and of sequelae of brain trauma or apoplexy as well as tumor diseases. ''

Characteristic of the known technical solutions

British Patent No. 1,039,113 describes N-substituted lactams of the general formula

V (CHJ C0 <2 m N ^ ₁

wherein η is 3, 4 or 5, m is 0, 1 or 2,

R 'is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl or aryl and R "is hydrogen or alkyl or R' and R" together with the nitrogen atom to which they are attached, a heterocyclic ring, for the treatment of motion sickness, hyperkinesia, hypertension and Epilepsy. Later, it was found that these compounds also have central nervous activity and affect memory (cf., British Patent No. 1,309,692). ,

German Offenlegungsschrift 2 507 576 describes a process for preparing 2-oxo-1-pyrrolidinyl! -Acetamide, the activating,

, ; - la - '. ,

has protective and restorative effects on the nerve cells of the cerebral cortex.

British Patent No. 1,309,692 describes N-substituted lactams having an effect on the memory and having the formula

^ -CH-CO-N

-j- / I V

V (X)

wherein X is hydrogen or alkyl, alkenyl or alkynyl each having 1-6 C atoms, ρ is an integer from 1 to 6, Y is hydrogen or alkyl, alkenyl or alkynyl each having 1-6 C-atoms or the cycloalkyl and R 'and R "independently of one another hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl or R ¹ and R" together with the nitrogen atom bound thereto mean a heterocyclic radical which may contain further heteroatoms, with the proviso that at least one of the radicals X and Y different from hydrogen.

Belgian Patent No. 887,487 describes the use of compounds of the formula

ii

wherein η is 0, 1, 2, 3 or 4, R is hydrogen or -NHCOCH ^ Q, wherein Q is 2-oxo-1-pyrrolidinyl which is substituted by (R ₉ ), and R is lower alkyl or, if η is 1, OH, or, if R is hydrogen, hydrogen to reduce the undesirable side effects of cytostatics in cancer therapy.

-Ib- Object of the invention ;

  j. "

The aim of the invention is the provision of new pyrrolidinone derivatives with increased effectiveness with regard to the improvement of memory performance and with a new spectrum of action, είητ finally the antitumor activity.

Explanation of the essence of the invention

The invention has for its object to find new Pyrrolidinonderivate with the desired properties and processes for their preparation.

In accordance with the invention, lactampetides of the formula I are prepared,

ο ₁₂

-CH-C-X-CH-C-N w-

¹ I '3'<

RR

V ³

Z is an alkylene radical which is unsubstituted or substituted by free or functionally modified hydroxy and / or by aryl and which forms a five-membered ring together with the amide group,

R is hydrogen, unsubstituted or substituted by aryl or by free or functionally modified hydroxy lower alkyl or aryl,

2 2 X oxygen or the group NR, wherein R is hydrogen or lower alkyl,

3 ''' ,

R is hydrogen, unsubstituted or substituted by free or functionally modified hydroxy, aryl, aminocarbonyl, mercapto, methylthio, free, alkylated or acylated amino, guanidino, free, esterified or amidated carboxy or imidazol-4-yl substituted

2 3

Lower alkyl or aryl or R and R together unsubstituted or

-IC-

trimethylene substituted by free or functionally modified hydroxy,

R is hydrogen or lower alkyl,

W one in each case with the carbonyl C atom to the rest of the formula II

(II)

bound radical of the formulas III, IV, V or .Vt, -

-. · ""'''-.-' ^:: '. o. ' : '·' .. 'o o';' .

'-'":; ^: . H -. '"",'' ^: ' I Ii

-CH-C- -CH-C-N-CH-C-

R ⁵ R ⁵ R ⁶ R ⁷

- (in) ^: (IV)

^ ' '. , ".

0 0 0 0 0 0 0

Il Il M Il Il Il Il

-CH-C-N-CH-C-N-CH-C-CH-C-N-CH-C-N-CH-C-N-CH-C-

(V) (VI)

wherein R, R and R independently of one another represent hydrogen or lower alkyl, R, R, R and R independently of one another hydrogen, unsubstituted or by free or functionally converted hydroxy, aryl, aminocarbonyl, mercapto, methylthio, free, alkylated or acylated Amino, guanidino, free, esterified or amidated carboxy or imidazol-4-yl substituted lower alkyl, or aryl or R and R together, R and R together, R and R together and / or R and R together are each independently unsubstituted or are trimethylene substituted by free or functionally modified hydroxy, and

12 13 R and R are independently hydrogen or lower alkyl or

12 13 · '

R and R together are tetra- or pentamethylene, 3-oxa-1, 5-pentylene or unsubstituted or substituted by oxo or methyl 3-aza-3-methyl-l, 5-pentylene, and salts of such compounds having at least one salt-forming Group, with the exception of those compounds of formula I wherein

Z is unsubstituted alkylene having 3 C atoms and at the same time R is hydrogen, unsubstituted alkyl having 1-4 C atoms, aryl or aryl-lower alkyl,

X is the radical NH,

R is aryl, unsubstituted alkyl or hydrogen,

4

R hydrogen, *

5 × 3 W is a radical of the formula ΪΪΙ in which R is identical to the Resf R

Meaning, and R ¹ and R are hydrogen

and salts of the latter compounds with at least one salt-forming group.

The unsubstituted alkylene radical Z has at least 3 and preferably not more than 17 C atoms and is substituted by at least one and up to four, preferably more than nuv 1 or 2, alkyl groups of trimethylene or tri-methylthio 1-position, 1,1-position or 3-position, wherein the 1-position of Trimethylenrestes denotes the bound to the nitrogen atom end.

Functionally modified hydroxy is esterified or etherified hydroxy. , ...

Esterified hydroxy is preferably by an organic, but also by an inorganic acid esterified hydroxy, especially acyloxy, besides also sulfonyloxy or halogen. Acyloxy is preferably optionally substituted hydrocarbylcarbonyloxy or hydrocarbyloxycarbonyloxy. Optionally substituted hydrocarbyl is here and below, in particular an aliphatic radical having 1-21, especially ¹ 1-11, especially 1-7 C atoms, a carbocyclic radical, ie a cycloaliphatic radical having 3-8, in particular 5 or 6, ring members and up to 21, preferably up to 11 C atoms, or a mono- or bicyclic aromatic radical with

, .- ⁴ - "". ', ·. '.

6 or 10 ring members and up to 21, preferably up to 15 carbon atoms, or a corresponding carbocyclic-aliphatic radical. In the abovementioned cycloaliphatic or. Aromatic radicals are preferably unsubstituted or substituted cycloalkyl radicals, in particular unsubstituted or lower alkyl-substituted cycloalkyl radicals, or phenyl radicals, e.g. Phenyl. · ,,. -.

In particular, sulphonyloxy is an aromatic, primarily monocyclic, aromatic, sulfonyloxy having at most 12 carbon atoms, e.g. Toluenesulfonyloxy, or lower aliphatic, preferably lower alkylsulfonyloxy.

The prefix "lower" here and in the following denotes a radical with 1-7, in particular 1-4 C atoms.

In particular, etherified hydroxy is optionally substituted, but not in the case of aryloxy, unsubstituted hydrocarbyloxy. !

Aryl is an unsubstituted or substituted carbocyclic aromatic radical. In the first place, aryl in the radicals R, R and W is unsubstituted or substituted phenyl, in the radical Z next also unsubstituted or substituted naphthyl.

The following aryl substituents may be mentioned in particular: lower alkyl, halogen and free or functionally modified hydroxy, but also free or esterified carboxy, oxo or unsubstituted or substituted phenyl. Aryl as Substitueiit of the alkylene radical Z carries as substituents irisbesondere halogen, especially fluorine, öder halophenoxy, especially 4-chloro-phenoxy.

Alkylated amino is primarily di-lower alkylamino, but also mono-lower alkylamino.

Acylated amino is unsubstituted or substituted hydro-

carbylcarbonylamino, especially Niederal'kanoylamino. In particular, carboxy substituted is unsubstituted or substituted hydrocarbyloxycarbonyl, especially lower alkoxycarbonyl.

Amidated carboxy is primarily carbamoyl, as well as an amino acid, e.g. an a-amino-lower alkanecarboxylic acid, or by mono- or di-lower alkylamino-amidated carboxy.

Unsubstituted lower alkyl R, R, R, R or R is preferably methyl, isopropyl, 1-methyl-propyl or isobutyl. Substituted lower alkyl R, R, R, R or R is preferably phenylmethyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, carbamoylmethyl, 2-carboxy-ethyl, 2-carbamoyl-ethyl or 4-amino-butyl, but also 3 Guanidino-propyl, 4-imidazolylmethyl, 4-hydroxyphenylmethyl, mercaptomethyl or 2-methylthio-ethyl. By free or functionally modified hydroxy-substituted trimethylene is substituted in particular in the 2-position. 3-Aza-3-methyl-1, 5-pentylene is preferably substituted by oxo in the 1-, 1- and 2- or 1- and 4-positions or by methyl, preferably in the 1- and 5-positions.

The configuration at optional asymmetric centers in a compound of formula I may be independently (D), (L) or (D ₅ L), but in the amino acid residues is preferably (L).

 The general terms used above and below preferably have the following meanings in the context of the present description:

Lower alkyl is especially methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, besides e.g. also sec. Butyl or tert. Butyl, furthermore n-pentyl, neopentyl, n-hexyl or n-heptyl.

Halogen is especially fluorine or chlorine, but may also stand for bromine or iodine.

Cycloalkyl is e.g. Cyclohexyl or cyclopentyl.

Diniederalkylamino is e.g. Dimethylamino or diethylamino.

Mono-lower alkylamino is e.g. Methylamino or ethylamino. Low-

alkanoylamino is e.g. Acetylamino or propionylamino. Lower alkoxycarbonyl is e.g. Methoxy or ethoxycarbonyl.

ι - . '

The invention also relates to the compounds of the formula I which can be used in particular as intermediates and have protected functional groups, in particular protected hydroxy, carboxy or amino.

Protecting groups, their introduction and removal are described for example in "Protective Groups in Organic Chemistry", Plenum Press,

London, New York 1973, and in "Methods of Organic Chemistry", w. ,

Houben-Weyl, 4th Edition, Vol. 15/1, George Thieme Verlag, Stuttgart 1974.

It is characteristic of protecting groups that they are light, ie without unwanted side reactions taking place, eg solvolytic, reductive, photolytic or even under physiological conditions . '' are split off.

Hydroxy protecting groups are e.g. Acyl radicals, as appropriate, e.g. by halogen, substituted lower alkanoyl, such as 2,2-dichloroacetyl, or acyl radicals of carbonic monoesters, especially tert-butyloxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or

; , 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl,

N- '. .. '' .. '·

furthermore trityl or formyl, or organic silyl or stannyl radicals, furthermore easily cleavable etherifying groups, such as tert-lower alkyl, e.g. tert -butyl, 2-oxa or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radicals, primarily 1-lower alkoxy-lower alkyl or 1-lower-alkylthio-lower alkyl, e.g. Methoxymethyl, 1-methoxyethyl, 1-ethoxy-ethyl, 1-methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl with 5-6 ring atoms, e.g. Tetrahydrofuryl or 2-tetrahydropyranyl or corresponding Thiaanaloge, and optionally substituted 1-phenyl-lower alkyl, such as optionally substituted benzyl or diphenylmethyl, wherein as substituents of the phenyl radicals, for example. Halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro come into question.

- 7 -

Carboxyl groups are usually protected in esterified form, such ester groups being readily cleavable under mild conditions. Contained in this way protected carboxyl groups

Preferred esterified groups are lower alkyl groups which are branched in the 1-position or are suitably substituted in the 1- or 2-position Preferred carboxyl groups which are present in esterified form include tert-lower alkoxycarbonyl, for example tert-butyloxycarbonyloxy, arylmethoxycarbonyl with one or more two aryl radicals, these being, for example, mono- or polysubstituted phenyl radicals, for example by lower alkyl, such as tert.-butyl, for example tert.-butyl, lower alkoxy, such as methoxy, hydroxy, halogeno, etc., chlorine, and / or nitro, as appropriate, for example as mentioned above, substituted benzyloxycarbonyl, eg 4-methoxybenzyloxycarbonyl, or 4-nitrobenzyloxycarbonyl, or optionally, for example as mentioned above, substituted ¹ -diphenylmethoxycarbonyl, eg diphenylmethoxycarbonyl or di (4-methoxyphenyl) -methoxycarbonyl, 1- Lower alkoxy lower alkoxycarbonyl such as methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl, 1-lower alkylthio-lower alkoxycarbonyl such as 1-methylthi omethoxycarbonyl or 1-Ethylthiöethoxycarbonyl, Aroylmethoxycarbonyl, wherein the aroyl group optionally, for example by

'Halogen, such as bromine, substituted benzoyl Barstellt, eg phenacyloxycarbonyl, 2-Halogenniederalkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) -ethoxycarbonyl, wherein the substituents independently an optionally substituted, for example substituted by lower alkyl, lower alkoxy, aryl, halogen, and / or nitro, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical, such as corresponding, optionally substituted lower alkyl, phenyl, alkyl, cycloalkyl or phenyl, for example 2-Triniederalkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl, or 2-Triarylsilylethoxycarbonyl such as 2-TriphenyIsi _/ lylethoxycarbonyl.

The organic silyl or stannyl radicals mentioned above and below preferably contain lower alkyl, in particular methyl, as substituents of the silicon or tin atoms. Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butyl-silyl, or appropriately substituted stannyl, e.g. Tri-n-butyl-stannyl.

Preferred protected carboxyl groups are tertiary lower alkoxycarbonyl such as tert-butoxycarbonyl, and especially optionally, e.g. As mentioned above, substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, especially 2- (trimethylsilyl) ethoxycarbonyl.

A protected amino group may e.g. in the form of an easily cleavable acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-en-1-yl-amino, silyl or stannylamino group or as azido group.

For example, in a corresponding acylamino group, acyl is the acyl radical of an organic carboxylic acid with e.g. up to 18 carbon atoms, especially an optionally, e.g. by halogen or aryl, substituted alkanecarboxylic acid or optionally, e.g. by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic monoester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl, or Propipn'y.l, halo-lower alkanoyl, such as 2-haloacetyl, in particular 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetyl, optionally, for example halo, lower alkoxy or nitro substituted benzoyl, e.g. Benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl branched at the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, especially tert.-lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals, which are preferably present

/ = '".- ;,. ^; . · -, 9 -., ^.,';;: '." :.

if, e.g. lower alkyl, especially tert.-lower alkyl, such as tert.butyl, lower alkoxy, such as methoxy, hydroxy, halo, e.g. Chlorine, and / or nitro, mono- or polysubstituted phenyl, such as optionally substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or substituted diphenylmethoxycarbonyl, e.g. Benzhydryloxycarbonyl or di (4-methoxyphenyl) methoxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) -ethoxycarbonyl wherein the substituents each independently represent an optionally substituted, e.g. lower alkyl, lower alkoxy, aryl, halo or nitro substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon residue with e.g. up to 15 C atoms, such as corresponding, optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, for example * 2-tri-lower alkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2- (din-butyl-methyl-silyl) -ethoxycarbonyl, or 2- Triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

Other acyl radicals which may be used as amino-protecting groups are also corresponding radicals of organic phosphorus, phosphine or

Phosphinic acids, such as dilower alkyl phosphoryl, e.g. Dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, e.g. Dicyclohexylphosphoryl, optionally

substituted diphenylphosphoryl, for example diphenylphosphoryl _t optionally substituted, for example nitro-substituted di- (phenyl-lower alkyl) phosphoryl, for example dibenzylphosphoryl or * Dir (4-nitrobenzyl) -phos, phoryl, optionally substituted Phenyloxyrphenyl-phosphonyl, zB'Phenyl * - oxyphenyl-phosphonyl , Diniederaikylphosphinyl, eg diethylphosphinyl, or optionally substituted diphenylphosphinyl, eg Dipheny1-phosphinyl.

· F. "/ '": - -: - ^ Λ'':-'; - '"": · · . '''Λ.'^.' ^:: - '

In an arylmethylamino group which represents a mono-, di- or in particular triarylmethylamino, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups are for example benzyl, diphenylmethyl and especially tritylamino.

, '' '*. An etherified mercapto group in an amino group protected with such a radical is primarily arylthio or aryl-lower alkylthio, wherein aryl is especially optionally, e.g. is phenyl substituted by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, j and / or nitro. A corresponding amino protecting group is e.g. 4-nitrophenylthio.

In a 2-acyl-lower alk-1-enyl radical useful as an amino-protecting group, acyl is e.g. the corresponding residue of a lower alkanecarboxylic acid, an optionally, e.g. by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro substituted benzoic acid, or in particular a carbonic monoester, such as a carbonic acid lower alkyl. Corresponding protecting groups are primarily 1-lower alkanoylprop-1-en-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, e.g. l-ethoxycarbonyl-prop-l-en-2-yl.

An amino group can also be protected in protonated form; suitable anions are primarily those of strong inorganic acids, such as hydrohalic acids, e.g. the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid in question.

ψ '  , ' "'

Preferred amino protecting groups are acyl radicals of carbonic monoesters, especially tert-butyloxycarbonyl, optionally, e.g. as indicated, substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or formyl.

, , ν.-ν - '; ;; : '::' .. ·. · :: .-.:. - 11 - '. '' ..; '' .. .. ' '. :, '

Salts of the compounds of the invention having salt-forming groups are primarily pharmaceutically acceptable non-toxic salts, such as those of compounds of formula I having acidic groups, e.g. with a free carboxyl and sulfo group. Such salts are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or .Calcium- '' '' 'salts, and ammonium salts with ammonia or suitable organic amines, wherein primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di - or polyamines, as well as heterocyclic bases for salt formation in question, such as lower alkylamines, eg Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine, 2-hydroxyethyl-diethyl-amine or tri (2-hydroxyethyl) -amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethylpiperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. Ν, Ν'-dibenzylethylenediamine, also pyridine-type bases, e.g. Pyridine, collidine or quinoline. Compounds of formula I having at least one basic group may include acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. Trifluoroacetic acid, as well as with amino acids such as arginine and lysine. In the presence of several acidic or basic groups, mono- or polysalts can be formed. Compounds of formula I with an acidic, e.g. free carboxyl group, and a free basic, e.g. an amino group, may also be in the form of internal salts, i. in zwitterionic form, or it may be a part of the molecule as an inner salt, and another part as a normal salt.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use, only the pharmaceutically acceptable, non- ^ toxic salts, which are therefore preferred.

The compounds of the formula I in which the functional groups ',' are in free, ie not in protected form, but carboxyl and hydroxyl groups are optionally present in physiologically cleavable, esterified form, and their pharmaceutically acceptable, non-toxic salts are valuable, pharmacologically active substances. In particular, they provide protection against the amnesiogenic effect of cerebral electroshock and an improvement in memory performance. Findings of this kind can be determined in the following learning tests:

One of these learning tests is a passive avoidance passive test, modified by Jarvik and Koop, Psychol. Rep. 211 221-224 (1967).

The test device consists of a large box (35 χ 20 χ 10 cm), which is connected by a sliding door with a small box (10 χ 10 χ 18 cm). While the small box is lit up by a lOO watt lamp from above, the big box is dark. The bottom of both compartments consists of an electrically conductive grate, the Git'terstäbe (6 mm diameter) are arranged at a distance of 13 mm. For training groups of each 10 'male mice with a body weight of 20-22 g individually placed in the brightly lit small box. Since mice have a spontaneous

'- ^'. ,

Prefer to have dark, most go within 30 seconds in the dark compartment. Once you have entered this completely, the sliding door is closed and a foot shock (1 mA, 50 Hz, 5 seconds) administered. The animals are immediately removed from the experimental apparatus. '

To test the learning effect (retest), the mice are again individually placed in the bright compartment after -24 hours and the time until they are completely in the dark compartment measured. Usually most of the animals stay over the entire observation time of 150 seconds

- 13 -

in the light compartment. The learning effect is largely abolished or the memory of the foot shock is at least partially wiped out if, as amnesiogenic treatment, a temporal electroshock treatment is connected immediately after the foot of the learning cycle. Electro-shock parameters: 50 mA, 0.4 seconds, 50 Hz, 0.6 milliseconds (pulse duration). , _;

To test and compare their protective effect against the amnesiogenic effect of the electric shock, the test substances will be dosed at 0.1 mg / kg, ί mg / kg, 10 mg / kg and 100 mg / kg (for each dose) 30 minutes prior to the learn session 10 mice used) as solution in physiological NaCl solution or physiological saline solution alone (= placebo) administered intraperitoneally and subjected the animals immediately after learning the electric shock treatment 24 hours later, the extent of the remaining in the lit box A comparison was made between the remaining learning effect and that of the other test substances as well as controls with sole administration of the particular solvent used and training without, as well as those with subsequent electroshock treatment A placebo-treated group without electroshock treatment serves to control learning in the avoidance test second with placeb o treated control group followed by electric shock treatment serves to monitor the extent of the amnesiogenic effect of the electric shock.

The above-mentioned effects can be detected, for example, after intraperitoneal administration of N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl- (L) -alaninamide in a dose range of 0.1 to 100 mg / kg.

To directly measure the improvement in memory performance, another passive avoidance test is used (Psychopharmacol., 63, 297-300, {19,79]):

The test device consists of a daylight normally lit box (50 χ 50 χ 50 cm) with an electrically conductive grid ^ whose bars (6 mm diameter) at a distance ^; each of 13 mm are arranged. In the middle of the grid is a wooden platform (10 mm high, 67 mm in diameter), which is surrounded by a plastic tube (20 cm high, 68 mm internal diameter). To perform the training, groups of 30 male mice each weighing 20-22g are used by placing one animal on the platform surrounded by the plastic tube, removing the plastic tube after 10 seconds, and measuring the time the animal descends and touching the grid with all 4 paws needed. When all 4 paws touch the grid, a foot shock (1 mA, 50 Hz, 1 second) is given. Within 10 seconds of the foot shock, the test substances are dosed at 3 mg / kg, 10 mg / kg and 30 mg / kg (30 mice are used for each dose) as a solution in physiological NaCl solution or its solvent (physiological sodium chloride solution = Placebo) intraperitoneally. Twenty-four hours later, on the basis of each animal's length of stay on the platform, the extent of improvement or deterioration of the learning effect is determined in comparison to the animals to which only the solvent had been applied for control. Thus, an improvement in memory performance, for example, after just ip administration of 10 mg / kg N - [(2-0xo-l-pyrrolidinyl) -acetyl] -glycyl- (L) -alaninamide show.

Because of these properties, the novel compounds appear to be useful in the treatment of cerebral insufficiency, in particular, memory disorders of various etiologies, such as senile dementia, multi-infarct dementia or dementia of the Alzheimer type, as well as sequelae of brain trauma or apoplexy.

:; · ..; - 15 -: '\. .. '·. · .. ·. ,. ; ^: . '.. ..

The new compounds also have a pronounced tumor-inhibiting effect. They not only inhibit the growth of tumors and reduce the number of tumors, but they also increase survival time. Two advantages of the compounds according to the invention over conventional cytostatic or cytotoxic drugs are their good tolerability and their reasoning that they do not reduce the quality of life of the tumor patients as nootropics but, on the contrary, help these patients to overcome their psychological problems. The compounds according to the invention can thus be used for the treatment of tumors, e.g. of the respiratory tract j in warm-blooded animals, including humans.

The antitumor effect of the new compounds can be. be shown by the following experiment:

In Syrian hamsters, papillary, epidermoid, and adenocarcinomatous tumors of the larynx, trachea, and lungs are produced by administration of diethylnitrosamine to the stomach (Papapoulo, G.H., and Schmidt-Ruppin, K.H., Oncology 33, 40-43 (1976)). Part of these tumorous hamsters are treated with a compound of formula I (e.g., twice a day for 5 days, 5 days per week for 4 weeks per week in a single dose of 20 mg / kg each), and the remainder of the hamsters are treated with a placebo. Three or four days after the end of treatment, all hamsters are killed. The respiratory tract is excised and, after appropriate preparation, examined microscopically for size, number and type of tumors therein. It is found that the size and number of tumors in the treated with a compound of formula I hamsters compared to the untreated hamsters is significantly lower.

In particular, the invention relates to compounds of the formula I in which Z is an alkylene radical having 3 to 17 carbon atoms which is unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy and / or an unsubstituted or substituted by halogen, lower alkyl, halogenophenoxy, hydroxy or lower alkoxy or naphthyl substituted and together with the amide group forms a five-membered ring, R is hydrogen, unsubstituted or substituted by a phenyl radical, hydroxy, lower alkoxy or lower alkanoyloxy lower alkyl or

2 '', '' phenyl, X is oxygen or the group NR, wherein R is hydrogen or lower alkyl,

R is hydrogen, unsubstituted or substituted by hydroxy, lower alkanoyloxy, a phenyl radical, aminocarbonyl, mercapto, methylthio, amino di- or mono-lower alkylminino, lower alkanoylamino, guanidino, carboxy, lower alkoxy carbonyl or imidazol-4-yl lower alkyl or

.- · '·:. ".: 2 3'. '.' · '' '

a phenyl radical, or R and R together unsubstituted or by

, ''. · ,. '- -'. .. ''.

Hydroxy, lower alkoxy or lower alkanoyloxy substituted trimethylene,

• 4 ": '.' ^: '''.,' V ''.

R is hydrogen or lower alkyl, ^

W is a radical of the formulas III, IV, V or VI bonded in each case with the carbonyl C atom to the radical of the formula II, in which R, R and R independently of one another represent hydrogen or lower alkyl, R, R, R and R independently of one another represents hydrogen, unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, a phenyl radical, aminocarbonyl, mercapto, methylthio, amino, di- or mono-lower alkylamino, lower alkanoylamino, guanidino, carboxy, lower alkoxycarbonyl or imidazol-4-yl Niederalkvl or a

4 5 6 7 8 ο

Phenyl, or R and R together, R and R together, R and R together or R and R together are each independently unsubstituted or substituted by hydroxy, lower alkoxy or lower alkanoyloxy trimethylene, and

12 13 R and R are independently hydrogen or lower alkyl or

12 13 R and R together tetra- or pentamethylene, 3-oxa-l, 5-pentylene

- 17 -

or unsubstituted or substituted by oxo or methyl .3-AzU-3-methyl-l, 5-pentylene, and salts of such compounds having at least one salt-forming group, with the exception of the previously excluded compounds of formula I, which are not the subject of the present invention.

The invention primarily relates to compounds of the formula I in which Z is an alkylene radical having 3 to 14 C atoms which is unsubstituted or substituted by hydroxy, lower alkanoyloxy and / or naphthyl or a unsubstituted or halogen- or halophenoxy-substituted phenyl radical, and together with the amide group forms a five-membered ring, R is hydrogen or unsubstituted or hydroxy or lower alkanoyloxy-substituted lower alkyl,

2 2 X is oxygen or the group NR, wherein R is hydrogen or C., -alkyl,

R is hydrogen, unsubstituted or substituted by hydroxy, lower alkanoyloxy, phenyl, 4-hydroxy-phenyl, aminocarbonyl, amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl or imidazol-4-yl lower alkyl, or phenyl, or

2 3 R and R together are unsubstituted or hydroxy-substituted trimethylene,

4 R is hydrogen or C 1 -C 4 alkyl,

W one in each case with the carbonyl C atom to the rest of the formula II

bonded radical of the formulas III, IV, V or VI, in which

6 8 10 R, R and R independently of one another represent hydrogen or C ₁ -alkyl,

5 7 9 11. ,

R, R, R and R independently of one another represent hydrogen, unsubstituted or substituted by hydroxy, lower alkanoyloxy, phenyl, 4-hydroxyphenyl, aminocarbonyl, amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl or imidazol-4-yl lower alkyl, or phenyl, or

"4, 5 6 7 8 9

R and R together, R and R together, R and R together and / or

10 11

R and R together are each independently unsubstituted or substituted by hydroxy or lower alkanoyloxy trimethylene, and

- 18 -

12 13 R and R are independently hydrogen or lower alkyl or

12 13 R and R together are tetra- or pentamethylene, 3-oxa-l, 5-pentylene or unsubstituted or substituted by oxo or methyl 3-aza-3-methyl-l, 5-pentylene, and salts of such compounds with at least a salt-forming group.

Mainly the invention relates to compounds of the formula I,

Z is a radical of formula VII,

III - C - C - C -. (VII)

I ₁₅ Il RHH

14 which is bound to the nitrogen atom with the C (R) atom, and

14 15. ·. ;

R and R independently of one another are hydrogen or C./1_alkyl, ν

, J. -H

R is hydrogen, naphthyl, unsubstituted or substituted by fluorine, chlorine, fluorophenoxy or chlorophenoxy phenyl, hydroxy or lower alkanoyloxy and

R is hydrogen, hydroxy or lower alkanoyloxy, R is hydrogen, unsubstituted or substituted by hydroxy C alkyl,

/ 2 2

X is oxygen or the group NR, where R is hydrogen or

Radkettiges C - alkyl stands, 1-J

R 3 is hydrogen or unsubstituted or substituted by hydroxy, phenyl, p-hydroxy-phenyl, aminocarbonyl or imidazol-4-yl lower alkyl,

4 R is hydrogen or straight-chain C ₁ "-alkyl, W a in each case with the carbonyl-C atom to the rest of the formula II

- 19 -

bound radical of the formulas III, IV, V or VI, '' in which ''. '' ^:: , - .. '', '.,' · ':, _:: -: "''''': -

R, R and R independently of one another represent hydrogen or straight-chain C _1-3 -alkyl,. , · · -.

R, R, R and R independently represent hydrogen or unsubstituted or substituted by hydroxy, phenyl, 4 ^ hydroxy-phenyi, aminocarbonyl or imidazole-4 * -yl lower alkyl, or, if

, W is formula III, R and R together, or when W is formula

fi 7>'^ ft IV, R and R together, or when W represents formula V "R and R together, or when W represents formula VI, R and R together represent an unsubstituted or substituted by hydroxy or lower alkanoyloxy substituted trimethylene, and

12 13. '' · '.-

R and R are independently hydrogen or C, -alkyl or

12 13 R and R together are S-oxa-1-yl-pentylene or S-aza-3-methyl-1,5-pentylene, and salts of such compounds having at least one salt-forming group.

Above all, the invention relates to compounds of the formula I.

14 '' '' '': '. - ''; Z is a radical bound to the nitrogen atom with the C (R) atom

- 14 15.

of the formula VII in which R and R, independently of one another, are hydrogen or C 1 -C 4 -alkyl, R is hydrogen, naphthyl, 4-fluorophenyl, 4-chlorophenoxyphenyl or hydroxyl and R is hydrogen, R is hydrogen,

X is oxygen or the group NH,

3 ^: 'R is hydrogen or C -C, -alkyl,

4. , '. , .1 ^. ·. , ...- R hydrogen,

W is a radical of the formulas III, IV, V or VI, in which

R, R, R and R are independently hydrogen or

R, R and R are hydrogen or R and R together are tri

12 ^iü 13 ¹ ^

methyl, R is hydrogen and R is C, -C, alkyl.

- 20 -

The invention particularly relates to the abovementioned compounds of the formula I in which X is the group NH and / or W is a radical of the formulas III or IV and / or R, R and R, and also R, independently

2 4 are each hydrogen or C, -alkyl and / or R, R, R,

8 10 ''

R and R are hydrogen.

The invention particularly relates to the compounds of the formula I in which Z is trimethylene or 2-hydroxytrimethylene, R, R, R and R are hydrogen, X is the group NH, W is a radical of the formulas III or IV,

5 6 7

wherein R is hydrogen or methyl and R and R is hydrogen

13. ,

and R is hydrogen or C "-alkyl, wherein the

5 configuration on CR when R is methyl, (D) or (L), in particular all of the abovementioned compounds in which Z is trimethylene, and salts of such compounds having at least one salt-forming group, especially the compounds of the formula I,

  1 '2 2 3

wherein Z is trimethylene, R is hydrogen, X is the group NR, R and R

2 3 4

Hydrogen or R and R together trimethylene, R is hydrogen, W is a radical of the formulas III, IV, V or VI, wherein R is hydrogen or C "alkyl or R and R together for trimethylene, R, R, R, R, R and R is hydrogen or R and R together are trimethylene

12 13

R, R is hydrogen or C-alkyl and R is hydrogen.

First and foremost, the invention relates to the compounds described in the examples, in particular N - [(2-oxo-1-pyrrolidinyl) -acetyl] -L-prolyl-glycyl-glycine-amide, but also N - [(2-oxo-1 -pyrrolidinyl) -acetyl] -glycyl- (L) -alanineamide and N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl- (L) -alanine-N-monoethyl-amide.

The erfindüngsgemässen compounds of formula I and salts of such compounds having at least one salt-forming group are obtained by methods known per se.

- 21 -

Of course, the above-mentioned compound group of formula I, wherein Z is unsubstituted alkylene having 3 C atoms and at the same time R is hydrogen, unsubstituted alkyl having 1-4 C atoms, aryl or aryl-lower alkyl, X is the radical NH, R in all the above-mentioned compound groups Aryl, unsubstituted alkyl or hydrogen,

R is hydrogen, W is a radical of formula III, wherein R is one with the

3 12 13

Rest R has identical meaning, and R and R are hydrogen, and salts of compounds of this compound group with at least one salt-forming group excluded, that is, the invention does not affect the latter compounds.

Compounds of the formula I and salts of such compounds which contain at least one salt-forming group are prepared, for example, by reacting

a) a compound of the formula VIII,

ο ο ο ₁₂

Il Il -I / R ..... _v ; ; /.- Ii-C ^ -,: / -. ·, YZC-NH-CH-CX-CH-CNWN ₁₃ (VIII)

; , K. Κ.ΙΛ.

in which Y is a nucleophilic leaving group and the other substituents have the abovementioned meanings, with the ability,

13 that functional groups present in the radicals Z, R, R or W, optionally protected if necessary by readily removable protecting groups intramolecularly cyclized to form the pyrrolidone ring, or,

b) a compound of the formula IX,

ο o

R - Z - N - CH - C - X - CH - C - N - W - I / (IX)

.1 I ₁ - I ₃ I ₄ \ ³ HRRR

- 22 -

19 wherein R represents a carboxyl group or an activated derivative thereof and also the amino group participating in the reaction may be present in activated form and the remaining substituents have the abovementioned meanings, with the proviso that in the radicals Z, R, R or W optionally present functional groups are optionally protected by readily cleavable protecting groups, cyclized intramolecularly to form the pyrrolidone ring or

c) a compound of the formula X,

(X)

wherein Z has the abovementioned meaning, with the proviso that functional groups present therein are optionally protected by readily cleavable protective groups, or a reactive form of this compound with a compound of formula XI,

⁰ ° 12

»H λ

Y-CH-C-X-CH-C-N-W-Nf (XI)

I ₁ I ₃ I ₄ ^ -

RRR)

wherein Y is a nucleophilic leaving group and the remaining substituents have the abovementioned meanings, with the proviso

13 that in the radicals Z, R, R or W existing functional groups

optionally protected by readily removable protecting groups, or,

- 23 -

d) a compound of the formula XII,

OH

(XII)

where η and ρ are independently 0 or 1 and A is the remainder

W or W, where W is a radical of the formulas III. IV or V a 'a

means, and the other substituents have the abovementioned meanings

13

with the proviso that optionally present in the radicals Z, R, R and A functional groups are protected by readily cleavable protecting groups, or a reactive carboxylic acid derivative of the compound of formula XII with a compound of formula

H-

(XIII)

wherein E is the radical of the formula -N-W- or the radical W, which is so

I / D

is defined, that when linking W and W, the remainder

3-D

and q and r independently of one another represent the number 0 or 1, with the proviso that r and q are each 1 and E is the radical -N-W-, if in the reactant of the formula XII ρ is 0

or that r is 1, q is 0 and E is the radical -N-W-,

R ⁴ when ρ is 1 and η is 0, or that r is 1, q is 0 and E is W, when ρ is 1, η is 1 and A is W, or that r is 0 when ρ is and η are each 1 and A is W, and in which the other substituents have the abovementioned meanings, with the proviso that in the radicals R and E

- 24 -

optionally present functional groups are optionally protected by readily cleavable protecting groups, or a derivative of the compound of formula XIII in which the group H-X-, H-E- or; H-N in reactive form, reacts, or

e) a compound of the formula I in which at least one of the radicals R,

R, R, R, R, R and R are hydrogen and the other substituents have the abovementioned meanings, with the proviso that functional groups present in a compound of the formula I, with the exception of the reacting amide group (n ) are optionally protected by readily cleavable protecting groups, or reacting a reactive derivative of this compound with an alkylating agent introducing the abovementioned radicals R, R, R, R, R and / or R, or

f) in a compound of formula I, wherein Z is one with the

14 C (R) atom bound to the nitrogen atom of the formula XV or

R ¹⁴ R ¹⁶ O Il Il Kj - ~~ \ j < ^ _- * - "

W ι _1β ι J ₁₁ . ι ι

R ¹⁵ HH (XV) (XVI)

wherein all substituents have the abovementioned meanings, with the proviso that in the radicals R, R, W, R and R optionally present functional groups are optionally protected by readily cleavable protecting groups, the keto group in the formulas XV or XVI, with a regioselective Reducing agent converted into a hydroxy group, or

XVI stands, R ¹⁴ 0 R ¹⁷ I Il I -C - • c - c - J " I H

- 25 -

g) the cyano group in a compound of the formula XVII,

V ο ο

-CH-C-X-CH-C-N-U-CN (XVII)

¹ I ¹ S ^! 4 RRR

wherein U is a radical of the formula XVIII, XIX, XX or XXI

-CH "" -CH ^- CN " ¹ CH ^- '

R ⁵ R ⁵ R ⁶ R ⁷

(XVIII) '(XIX)

0. 0. 0 0 0

Il Il Il II II

-CH-C-N-CH-C-N-CH- * -CH-C-N CH-C-N-CH-C-N-CH-

R ⁵ R ⁶ R ⁷ R ⁸ R ⁹ R ⁵ R ⁶ R ⁷ R ⁸ R ⁹ R ¹⁰ R ¹¹ (XX) '(XXI)

and wherein all substituents have the meanings given above, converted into an amide group or

h) the oxime group in a compound of the formula XXIT, Ο _χ Ο 0 R ¹³

\ Il Il I

^ N-CH-C-X-CH-C-N-U-C = N-OH (XXIII)

Z 1 · 3 4

R R R.-.-.

wherein the substituents have the abovementioned meanings, converted by a Beckmann rearrangement in an amide group, or

i) esterifying or etherifying free hydroxy in a compound of the formula I which has at least one free hydroxyl, carboxy or amino group, esterifying or amidating free carboxy or

- 26 -; , '.':,

alkylating or acylating free amino and, after carrying out the processes described under a) to h), cleaving off any protecting groups present and separating if desired stereoisomer mixtures and, if desired, a resulting compound having at least one salt-forming group in a salt or a salt obtained transferred the free connection.

Process a) (intramolecular cyclization of a compound of formula VIII): A nucleophilic leaving group Y is in particular a hydroxy group esterified with suitable acids, e.g. a sulphonate, such as mesylate or tosylate, especially halogen, such as bromine or iodine, but especially chlorine.

The reaction is carried out with the aid of a base, using preferably equimolar amounts of this base. As bases, in particular, e.g. Metal hydroxides, carbonates or alcoholates such as alkali metal or alkaline earth metal hydroxides or alcoholates, e.g. Sodium or potassium hydroxide or sodium tert-butylate, or alkali metal carbonates or salts, especially alkali metal salts, secondary amides, e.g. 2-oxopyrrolidine sodium, or strong base ion exchangers, e.g. Dowex 1 (Registered Trade Mark), as well as hydrides or amides; e.g. Alkali metal hydrides or amides, such as sodium hydride or amide or lithium diisopropylamide. >

The Ringschiussreaktion is preferably conducted in an inert organic solvent, if desired or necessary, carried out under cooling 'or heating, for example in a temperature range of about -8O ⁰ C to about +150 ⁰ C, especially between 0 ⁰ C and 100 ⁰ C.

In general, the reaction conditions should be selected so that the intramolecular ring-closing reaction is favored over intermolecular reactions of the same type of reaction which would lead to the formation of dimers or the like. For this purpose one can, for example, work in greater dilution, if necessary.

- 27 -

The activation with the aid of the base can be carried out at the same or a different temperature than the actual ring-closing reaction.

Especially when using a very strong base, e.g. Lithium diisopropylamide, activation with the base ("metalation") occurs at a lower temperature (e.g., -80 ° C) than ring closure. In this case, one can e.g. let the reaction vessel slowly warm up after the metalization has taken place,

When choosing the solvent, the type of base to be used must also be taken into account. Reactions using alkali metal hydroxides are preferably carried out in dimethyl sulphoxide or in alcohols such as lower alkanols, eg anhydrous ethanol at boiling temperature, reactions using Alcoholates are preferably carried out in ethers, in particular cyclic ethers, using sodium tert-butylate, for example in dioxane room temperature. Ring-closing reactions with, for example 2-oxo-pyrrolidin-sodium are carried out, inter alia, in a mixture of a cyclic ether and an aromatic hydrocarbon, for example a dioxane-toluene mixture, at a temperature between room temperature and 60 ⁰ C.

The cyclization with the aid of an ion exchanger according to the invention is carried out in particular in an alcohol, e.g. Lower alkanol, e.g. Ethanol, at room temperature. :

The starting materials of formula VIII can be prepared by methods known per se, e.g. by acylating the free amino group of a peptide amide of the formula XXIII,

0. P

Μ Ii R:

H is N-CH-CX-CH-CNWN. ₁₃ (XXIII)

I ₁ II ₄ ^ RR ₃ R

wherein the substituents have the abovementioned meanings, with the proviso that free functional groups present therein, if

, , , - 28 -. , , ', .-;. .... v ^:. '

. ' - '.'-. ,

desirably present in protected form with an acid chloride of formula XXIV;

^cl · ·

γ - Z - C

wherein Y and Z have the abovementioned meanings, e.g. Y is chlorine, with the proviso that in the rest Z existing free functional groups are optionally protected by readily cleavable protecting groups, and subsequent removal of the protective groups.

Process b) (intramolecular cyclization of a compound of the formula IX):

Activated carboxylic acid derivatives of a compound of formula IX are primarily reactive activated esters or reactive anhydrides, further reactive cyclic amides; In this case, reactive derivatives of acids of the formula IX can also be formed in situ .

Activated esters of acids, especially at the linking carbon atom of the esterifying radical, are unsaturated esters, e.g. from the vinyl. ester type, such as actual vinyl esters (which can be obtained, for example, by transesterification of a corresponding ester with vinyl acetate, activated vinyl ester method), carbamoylvinyl esters (which can be obtained, for example, by treating the corresponding acid with an isoxazolium reagent; Oxazolium or Woodward method), or 1-lower alkoxyvinyl ester (which can be obtained, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or amidino-type esters, such as Ν, Ν'-disubstituted amidinoesters (which may be obtained by, for example Treating the corresponding acid with a suitable Ν, Ν'-disubstituted carbodiimide, for example Ν, Ν'-dicyclohexylcarbodiimide, obtainable, carbodiimide method), or N, N-disubstituted. amidinoesters (which can be obtained, for example, by treating the corresponding acid with an N, N-disubstituted cyanamide, cyanamide method), suitable aryl esters, in particular by electron

attractive substituents suitably substituted phenyl esters (which, for example, by treating the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonyi-phenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlor phenol or 4-phenyldiazophenol, in the presence of a condensing agent, such as N, N'-dicyclohexylcarbodiimide; activated aryl ester method), cyanomethyl ester (obtained by treating the corresponding acid with chloroacetonitrile in the presence of a base cyanomethyl ester method), thioesters, in particular optionally, for example by nitro, substituted phenyl thioester (which can be obtained, for example, by treating the corresponding acid with optionally substituted, for example by nitro, substituted thiophenols, inter alia by means of the anhydride or carbodiimide method, activated thiolester method), amino or amido esters (For example, by treating the corresponding acid with an N-hydroxy-amino or N-hydroxy-amido compound such as N-hydroxy-succinimide, N-hydroxy-piperidine, N-hydroxyphthalimide or 1-hydroxy-benzotriazole, eg according to the anhydride or carbodiimide method, activated N-hydroxy ester method) or silyl esters (which can be obtained, for example, by treating the corresponding acid with a silylating agent, eg hexamethyldisilazane).

Anhydrides of acids of formula IX may be symmetrical or preferably mixed anhydrides of these acids, e.g. Anhydrides with inorganic acids, such as acid halides, in particular acid chlorides (which can be obtained, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride, acid chloride method), azides (which, for example, from a corresponding acid ester, the corresponding hydrazide and its treatment tni » nitrous acid; azide method), anhydrides with carbonic acid derivatives, as with corresponding esters, eg Kohlensiederiederalkylhalbestern (which, for example, by treating the corresponding acid with halogen, such as chloroformic acid-n'iederalkylestern., Or with a l-lower alkoxycarbonyl-2-lower alkoxy-l, 2-dihydro-quinoline, for example l-lower alkoxycarbonyl-2-ethoxy-l , 2-dihydroquinoline

'' '·.' '. - 30 - ·,

can; Mixed O-alkyl-carbonic anhydride method), or anhydrides with dihalogenated, in particular dichlorinated, phosphoric acid (which can be obtained, for example, by treating the corresponding acid with phosphorus oxychloride, phosphorus oxychloride method), or ... anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (which can be obtained, for example, by treating the corresponding acid with an optionally substituted lower alkane or phenylalkanecarboxylic acid halide, eg phenylacetic, pivalic or trifluoroacetic acid chloride, mixed carboxylic acid anhydride method or with organic sulfonic acids

(which may be obtained, for example, by treating a salt such as an alkali metal

salt, the corresponding acid, with a suitable organic. *

Sulfonic acid halide, such as lower alkane or aryl, e.g. Methane or p-toluenesulfonyl chloride, can be obtained; Mixed acid sulfoacid anhydride) and symmetrical anhydrides (which can be obtained, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethylaminopropyne; symmetrical anhydride method).

Suitable cyclic amides are in particular amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, e.g.

Imidazole (which is, for example, by treating the corresponding acid with

· .. '·,

Ν, Ν'-carbonyldiimidazole; Imidazolide method), or pyrazoles, e.g. 3,5-dimethyl-pyrazole (which can be obtained, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).

The amino group participating in the reaction in a starting material of the formula IX is preferably present in free form, in particular if the carboxy group reacting therewith is in a reactive form, but it may also itself be derivatized, ie for example. by reaction with a phosphite such as diethyl chlorophosphite, 1,2-phenylene-chlorophosphite, ethyl-dichlorophosphite, ethylene-chlorophosphate; phit or tetraethylpyrophosphite. _y

·: ·. ''^; . ' · ': " ^3l -. ''. V.. '.:' - Γ-. ^Ν -; '. {: /' Ν .v '^ V · - ^.:

Protecting groups of optionally present functional groups are e.g. the above-mentioned protection groups.

The ring closure reaction may be carried out in a manner known per se, the reaction conditions depending primarily on whether and how the carboxyl group participating in the reaction is activated, usually in the presence of a suitable solvent or diluent or a mixture of such and, if so necessary, in the presence of a condensation agent which, for example, if the person participating in the reaction, the carboxyl group is present as an anhydride, and an acid-bindendes- may agent, with cooling or heating, for example in a temperature range of about -30 ⁰ C to about +200 ⁰ C, in a closed reaction vessel and / or in the atmosphere of an inert gas, for example nitrogen. -

In general, the reaction conditions should be selected so that the intramolecular ring-closing reaction is favored over intermolecular reactions of the same type of reaction which would lead to the formation of dimers or the like. For this purpose one can, for example, work in greater dilution, if necessary.

, The reaction may e.g. be done by connecting

.19

of the formula IX, wherein R is an inactivated carboxyl group, and the remaining radicals optionally in protected form have the abovementioned meanings, optionally in the presence of a dehydrating agent, for example a Ν, Ν'-disubstituted carbodiimides, such as dicyclohexylcarbodiimide, and optionally additionally in the presence of an N-hydroxy-amine or N-hydroxy-amide, for example N-hydroxy-succinimide, heated in an anhydrous inert solvent, for example to 5O ⁰ C-ISO ⁰ C.

.19 Compounds of formula IX, wherein R is an activated carboxyl group, react in an anhydrous solvent even at lower temperatures, for example -20 ° to +50 ⁰ C, to form the 2-oxo-pyrrolidine ring. Preferably, one goes from such

, - 32 - .-. · .- .; .-ν ':'.,

activated carboxylic acid compounds of the formula IX, wherein the amino group adjacent to the radical Z is in protected form and then releases the amino group in situ, whereupon the cyclization occurs.

A preferred embodiment of process b) is the heating of a carboxylic acid of formula IX in hexamethyldisilazane.

^v 19

The compounds of formula IX wherein the xyoxyl group R is in protected form, i. as the radical R, e.g. as 2-trimethylsilylethyl-carbonyl, e.g. by N-alkylating a compound of formula XXIII or a suitable derivative thereof, e.g. an azomethine or the alkali metal salt of a benzenesulfonamide, with a compound of the formula XXV,

-R ¹⁹ - ZY (XXV)

a ..

Wherein R is a protected carboxyl group and Z and Y are the

have the above meanings. ,

Process c) (N-alkylation of the 2-oxopyrrolidine of the formula X):

A reactive form of a compound of formula X is especially a metal compound, primarily an alkali metal compound, e.g. a sodium, potassium or lithium compound thereof, which is e.g. by the action of a suitable base, e.g. an alkali metal hydroxides, e.g. Sodium hydroxide, an alkali metal alcoholate, e.g. lower alkanolate, such as -methylate, -ethylate or tert -butylate, an -hydride, -amide, e.g. Sodium hydride, sodium amide or lithium diisopropylamide, or an alkali metal hydrocarbon compound, e.g. Butyllithium, can produce.

'. "..' s - 33 - '. · - - -" · .V.; .

The nucleophilic leaving group Y corresponds to the group Y mentioned in process a) and is especially chlorine or bromine.

The reaction is preferably carried out in an anhydrous or, depending on the base used, aprotic solvent at temperatures between about -80 ⁰ C and +150 ⁰ C and similar to methods a) or e).

The starting compounds of the formula XI are obtained by acylating a compound of the formula XIII in which q and r are both 1 with an acylating agent of the formula XXVI,

Y-CH- (Z (XXVI)

"'I₁ egg'- ..' :

^R. '"·

wherein Y and R have the abovementioned meaning, with the proviso that present in the radical R free functional groups, if necessary, in a protected form, and, if desired, subsequent cleavage of the protective group (h) accessible.

The starting compounds of the formula X are known or can

e.g. by cyclization of a compound of formula XXVII or an activated carboxylic acid derivative thereof,

HOOC-Z-NH ₂ (XXVII)

wherein Z has the abovementioned meaning, with the proviso that, if necessary, protected free functional groups therein, are obtained analogously to process b) and deprotection.

The cyclization of a free acid of formula XXVII succeeds in many cases by heating to 200-250 ° without solvent and Kugelrohr distillation.

- 34 -

Method d) (formation of a peptide or ester bond):

Reactive carboxylic acid derivatives of a compound of the formula XII . Reactive esters, anhydrides or amides are analogous to those mentioned in process b),. ,

As mentioned in b) derivatives of acids of formula XII can also be formed in situ. So you can, for example Form in, Ν'-disubstituted amidinoesters in situ, by reacting the mixture of the starting material of formula XIII and the acid of formula XII in the presence of a suitable. Ν, Ν'-disubstituted carbodiimides, e.g. Ν, Ν'-Dicyclohexylcarbodiimid, brings to reaction. Furthermore, amino or imido esters of acids of the formula XII in the presence of the starting material of the formula XIII to be acylated can be formed by reacting the mixture of the corresponding acid and amino precursors in the presence of a; Ν, Ν'-disubstituted carbodiimides, e.g. N, N'-dicyclohexylcarbodiimide, and an N-hydroxyamine or N-hydroxyamide, e.g. N-hydroxy ·: · succinimide, optionally in the presence of a suitable base; e.g. 4-dimethylamino-pyridine. '· ·, .V

A derivative of the compound of formula XIII wherein the amino group participating in the reaction is in a reactive form may e.g. by reaction with a phosphite, e.g. one of those mentioned in process b) are produced. A reactive form of a compound of formula XIII is e.g. also a carbamic acid halide or an isocyanate, wherein the amino group participating in the reaction in a compound of formula XIII to halocarbonyl, e.g. Chlorocarbonyl, is.t or isocyanato is present, in the latter case, only compounds of formula I are accessible, which carry a Wasser'stoffatoni on the nitrogen atom of the amide group formed by the reaction. Another reactive form of a compound of formula XIII wherein r is 0 is e.g. a urea of the formula / XXVIH,,. , ,

- 35 -

-C-N. ' "

(XXVIII)

12, 13, 12

worm R and R have the abovementioned meanings, or, when R and R are methyl, dimethylformamide.

For example, when equimolar amounts of such ureas and the free acids of the formula XII are heated, the compounds of the formula I are obtained in good yield. ;

The acylation of a compound of formula XIII or a reactive derivative thereof with a compound of formula XII or a reactive acid derivative thereof may be carried out in a manner known per se, the reaction conditions depending more on the type of acylating agent used, more usually - '. in the presence of a suitable Lösüngs- or diluent or a mixture of such, and, 'if necessary, in ^v presence of a condensing init rock which, for example when using an anhydride as a ". acylating agent optionally also be an acid-binding agent may be, while cooling or heating , For example, in a temperature range of about -30 ⁰ C to about +150 ⁰ C, in a closed reaction vessel and / or in the atmosphere of an inert gas, for example nitrogen.

The starting materials of formulas XII and XIII are known or may be prepared by methods known per se, e.g. analogous to the methods described in this application.

Process d) also encompasses the embodiment in which first: a carboxylic acid of the formula XIIv in which η and ρ is 1, is reacted with a compound of the formula XIII in which r is 0, to give an ammonium salt of the carboxylic acid of the formula XII, and the ammonium salt obtained in this or another way thermally dehydrated to form a compound of formula I, eg analogous to that described in British Patent 1 309692.

- 36 - '

Process e) (N-alkylation of a compound of the formula I):

An alkylating agent which introduces R ", R '', - R, R, R, R or R is, in particular, a compound in which one of these radicals is bonded to the abovementioned nucleophilic leaving group Y.

The compound of the formula I is generally first brought into a reactive form with the aid of a base. It is preferable to use equimolar amounts of base, for example one of the bases mentioned in process a). Basically, but usually unnecessary, one can also use even stronger bases, eg, metal hydrocarbyl compounds, such as alkali metal lower alkyl compounds, eg, butyllithium, or activation can be achieved by using weaker bases under phase transfer conditions or in the presence of suitable complexing agents for the base cation, such as crown ethers . eg 18-crown-6. , ⁱ ~. , , , ''. ' , '

The reaction is preferably carried out in an inert organic solvent, if desired or necessary, carried out under cooling or heating, for example in a temperature range of about -80 to about +150 G ^{0 0} C, especially between 0 ⁰ C and 100 ⁰ C.

When choosing the solvent, in particular, the type of base to be used must be taken into account. Reactions with the use of alkali metal hydroxides are preferably carried out in dimethyl sulphoxide or in alcohols, such as lower alkanols, eg anhydrous ethanol at boiling temperature, reactions using alcoholates are preferably carried out in ethers, in particular cyclic ethers, using sodium tert-butylate, for example in dioxane at room temperature. Alkylation reactions using, for example, 2-oxopyrrolidine sodium can be carried out, inter alia, in a mixture of a cyclic ether and an aromatic hydrocarbon, eg a dioxane-toluene mixture, at a temperature between room temperature and 60 ^° C. The actual alkylation reaction may be at the same or different temperature than the activation

with the Hasp, in particular when using very strong B. iscn, such as lithium diisopropylamide or butyl lithium, the activation of Ausgangsverbinduhg of formula 1 with the base ("metallation ¹ ! ¹ ) at a lower temperature (eg, -80 ° C) than In this case, the alkylating agent can be added to the reaction vessel only after the end of the metallation and allowed to warm up slowly, Such metallation reactions with very strong bases are carried out in an inert, aprotic solvent and under protective gas, for example in a hydrocarbon, eg Hexane, benzene, toluene or xylenes, a weakly polar ether, eg diethyl ether, tetrahydrofuran or dioxane, or an acid amide, eg hexamethylphosphoric triamide, or mixtures thereof The reaction temperature is between about -80 ° and about room temperature, depending mainly on the melting point of the solvent or Solvent mixture and from the Re activity of the respective metallating reagent in the chosen solvent, but also on the solubility and the reactivity of the substrate.

Amide groups -CO-NH- ^ in a compound of formula I which are not intended to be alkylated can be prepared in a manner known per se, e.g. in the form of the N-biphenylmethyl derivative or an N-methoxybenzyl derivative, e.g. a 2,4-dimethoxy or 2,4,6-trimethoxy-benzyl derivative.

Further details for carrying out metallation and alkylation reactions analogous to those described above are given e.g. described in Houben-Weyl, Methods of Orgartische Chemie, Volume XI'll / l, Thieme Verlag, Stuttgart 1970.. :

Method f) (reduction of a keto group in the radical Z):

Such regioselective reducing agents can be used which under the reaction conditions reduce an isolated keto group sufficiently faster than amide groups.

- - 38 -

There are many borohydrides, such as alkali metal borohydrides, in particular sodium borohydride, lithium borohydride or sodium cyanoborohydride, or some aluminum hydrides, such as sterically.: Hindered alkali metal-lower alkoxyaluminum hydrides, z * B. Lithium tris-tert-butoxy-aluminum hydride. _

The reduction may also be carried out with hydrogen in the presence of certain heavy metal catalysts, e.g. Raney nickel, platinum or palladium catalysts, or Meerwein-Ponndorf-Verley with the help of '. Aluminum alkanolates, preferably aluminum 2-propoxide or: -ethanolat be performed. '

The reduction is preferably carried out with stoichiometric amounts or, if it is necessary due to undesired side reactions, for example with the Lösuijgsmittel, a meaningful excess of the reducing agent in an inert solvent at temperatures between -8O ⁰ C and +180 ⁰ C, preferably between 2O ⁰ C and +100 ⁰ C, if necessary, under-shielding gas, such as argon, carried out.

The starting compounds may be prepared by methods known per se, e.g. those described in, this application. The 2,3- or 2,4-dioxo-pyrrolidine ring may e.g. are prepared by a Dieckmann condensation starting from a compound of formula XXXI or XXXII,

0 ⁰ R ¹⁷

Il / 0 II _y

R / - (XXXI) (XXXII)

20 worm R is a radical of the formula XXXIII

-39-

° / · 9 · M2 ^;: . ""'

-CH-C-X-CH-C-N-W-N γ-, (ΧΧΧΙΙΙ)

or a suitably completed part thereof, and all other substituents have the meanings given above.

'14''15 ^'·':::. '. When R and R are hydrogen, a suitably completed portion of a group of formula XXXIII is preferably ethoxycarbonylmethyl. ,

Process g) (conversion of a cyano group into the amide): The conversion can be effected by partial hydrolysis, in the sense of a Graf-Ritter reaction or by way of carboxylic ester salts. The conditions for the hydrolysis of a compound of formula XVII must be chosen so that the reaction can be stopped at the stage of the amide and not the free carboxylic acid is formed. For this purpose most suitable is the hydrolysis with acids, it being possible, depending on the substituents present in a compound of the formula XVII, to choose between 80% strength sulfuric acid (with heating); Pblyphosphoric acid (at 110-150 °), hydrogen bromide / glacial acetic acid (room temperature), formic acid (without solvent), hydrogen chloride gas in ethereal solution followed by addition of water or aqueous hydrochloric acid, or boron halides / 1 equiv. Of water.

Preferably using an ion exchange resin, for example LewatiteMM 504 (see German Offenlegungsschrift 2,507,576). AmberIi or te ^v - ^/ IRA 400th

In some cases, the alkaline hydrolysis succeeds, but the method of Radziszewski with hydrogen peroxide in the presence of alkalis at moderate temperature is usually more successful.

With the help of the Graf-Ritter reaction, it is possible to prepare N-substituted amides from the nitriles of the formula XVII.

For this purpose, the nitriles are added in the presence of a strong acid, vor '.' 85-90% sulfuric acid, or else polyphosphoric acid, formic acid, boron trifluoride or other Lewis acids, but not aluminum chloride, with compounds which are acidic in nature. Medium can form carbenium ions, e.g. with olefins or

Alcohols * · .. '· \ -.... - ... / '.;;''-''' l · -: '.-.'' ^:: ' ''.

Instead of using a strong acid, one can also catalyze with mercury (II) nitrate and then reduce it with sodium borohydride.

The carboxylic acid ester imides are obtained e.g. by acid-catalyzed addition of alcohols to the nitriles .. From the Esterimiden the amides are obtained in the sense of a Pinner cleavage.

Nitriles of the formula X \ ^r II can be prepared, for example, by a Kolbe synthesis from the corresponding primary halides with cyanide ions in the sense of a nucleophilic substitution.

It is preferable to use e.g. a primary halide to copper cyanide in dioxane (see German Offenlegungsschrift 2 507 576). The primary halides are obtained e.g. from the primary alcohols by means of thionyl chloride (see German Offenlegungsschrift 2 507 576). Preferably, cyanomethylene-terminated nitriles of formula XVII are obtained by reaction of a compound of formula XII in which ρ is 1 and, if η also is 1, A is W · with aminoacetonitrile, which is commercially available the methods described for method d).

Method h) (Beckmann rearrangement):

The rearrangement of compounds of formula XXII, wherein

'.'"13 ^: ''. '.' - ''.'-' ^: ''.'-·'".'' ^: · '''-...'. · ''. ". ". R is lower alkyl, can be carried out under the known conditions of the Beckmann rearrangement, for example with concentrated sulfuric acid, hydrogen halides, polyphosphoric acid, thionyl chloride, formic acid, Tosylchiorid in pyridine, copper., Alkali metal

- 41 -

Chlorides, iron (II) or aluminum chloride, trifluoroacetic acid or "Japanese acid earth". Preferably, one goes, but of oximes

13, wherein R is trans to the hydroxy group of the oxime moiety, and in this case uses catalysts which cause as little as possible isomerization, such as phosphorus (V) chloride in ether or benzene at low temperature.

The rearrangement of compounds of formula XXII wherein R is hydrogen is best carried out with polyphosphoric acid or boron trifluoride. In this case, the configuration of the oxime does not matter. ^::.

The oximes of formula XXII are prepared by methods known in the art, e.g. accessible by reaction of the corresponding aldehydes or ketones with hydroxylamines. ^.; ,

Procedure i) (transformations within the definition of the end products):

The compounds of the formula (I) which can be obtained according to the invention can be converted into other compounds of the formula (I) in a manner known per se. / V::

In the compounds of the Eormel (t), which have at least one free hydroxyl group, this can be etherified according to methods known per se or 'esterified (acylated). Free carboxy can be esterified or amidated. Free amino can be alkylated or acylated, with the! Alkylation analogous to the etherification and the acylation is carried out analogously to the esterification of a hydroxyl group.

Suitable agents for etherifying a hydroxyl group or esterifying a carboxyl group include, for example, corresponding di-azo compounds such as optionally substituted diazo-lower alkanes, e.g. Diazomethane, diazoethane, diazo-n-butane or diphenyldiazomethari. These reagents are used in the presence of a suitable inert solution.

by means of such as an aliphatic, cyclic, or aromatic ;: hydrocarbon, such as hexane, cyclohexane, benzene, or toluene, of an ihalpgferiierten aliphatic hydrocarbon, e.g. Methylene chloride, or an ether such as a di-lower alkyl ether, e.g. Diethyl ether, or of a cyclic ether, ζ.B. Tetrahydrofuran or dioxane, or a solvent mixture, and depending on the diazo reagent, with cooling at room temperature or with gentle heating, further, if necessary, in a closed vessel and / or under an inert gas, e.g. Nitrogen atmosphere, γ applied.

Further suitable agents for etherifying a hydroxyl group or for esterifying a carboxyl group in a compound of the formula I are esters of corresponding alcohols, primarily those with strong inorganic or organic acids, such as mineral acids, e.g. Hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid, furthermore sulfuric acid, or halosulfuric acid, γ e.g. Fluorosulfuric acid, or strong organic sulfonic acids, as appropriate, e.g. by halogen, such as fluorine, substituted lower alkanesulfonic acids, or aromatic sulfonic acids, such as e.g. optionally substituted by lower alkyl, such as methyl, halogen, such as bromine, and / or nitro-substituted benzenesulfonic acids, ζ..B. Methanesulfone, trifluoromethanesulfonated p-Toluolsülfonsäure. Such esters are i.a. Lower alkyl halides, di-lower alkyl sulphates such as dimethyl sulphate, also fluoro, sulphonic acid esters such as lower alkyl esters, e.g. Fluorosulfonic acid methyl ester, or optionally halo-substituted methanesulfonic acid lower alkyl esters, e.g. Trifluoromethanesulfonate. They are usually in the presence of an inert solvent, such as an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Methylene chloride, an ether such as dioxane or tetrahydrofuran, or a mixture. It is preferable to use suitable condensing agents, such as alkali metal carbonates or bicarbonates, e.g. Sodium or potassium carbonate or bicarbonate (usually

together with a sulfate), or organic bases, as usual

- 43 -

sterically hindered Triniederalkylamine, for example N /, N ^ diisopropyl-N-ethyl-amine (preferably together with halosulfonic acid-lower alkyl or optionally halogen-substituted Methansulfonsäureniederalkylestern), with cooling, at room temperature or with heating, for example at temperatures of about -2O ⁰ C. to about 50 ⁰ C and, if necessary, in a closed vessel and / or in an inert gas, eg nitrogen atmosphere, is worked.

By phase transfer catalysis [see, e.g. Dehmlow, Angewandte Chemie, 86, 187 (1974)], the etherification reaction described above can be significantly accelerated. Quaternary phosphonium salts and in particular quaternary ammonium salts, such as optionally substituted tetraalkylammonium salts, may be used as phase transfer catalysts.

• ^v '''

halides, e.g. Tetrabutylammonium chloride, bromide or iodide, or benzyl triethyiammonium chloride, can be used in catalytic or up to equimolar amounts. As the organic phase may be any of the water-immiscible solvent, for example, 'one of the optionally halogenated, such as chlorinated, lower aliphatic, cycloaliphatic or aromatic hydrocarbons, such as tri- or tetrachlorethylene, tetrachloroethane, carbon tetrachloride, chlorobenzene, toluene or xylene. The alkali metal carbonates or bicarbonates, suitable as condensing agents, e.g. Potassium carbonate or bicarbonate of sodium, alkali metal phosphates, e.g. Potassium phosphate, and alkali metal hydroxides, e.g. Sodium hydroxide may be added titrimetrically to base-sensitive compounds of the reaction mixture, e.g. by means of a titration machine, so that the pH during the etherification between about 7 and about

Further agents for etherifying a hydroxyl group or esterifying a carboxyl group in a compound of the formula I are corresponding trisubstituted oxonium salts (so-called seaweed salts), or disubstituted carbenium or halonium salts, in which the substituents are the etherifying radicals, for example trichloride radicals.

Alkyloxnniumsalze, and Diniederalkoxycarbenium- or Diniederalkyl ^ halonium salts, in particular the corresponding salts with complex fluorine-containing acids, such as the corresponding Te'trafluorborate, Hexafluorphosphate, Hexaf1uorantimonate, or Hexachlorantimonate .. Such Reagentieh are, for example trimethyloxonium or Triethyloxonium hexafluoroantimonate, hexachlorantimonate hexafluorophosphate or tetrafluoroborate, Dimethoxycarbeniumhexafluor phosphate or Dimethylbromoniumhexäfluorantimonat. It is preferable to use these etherifying agents in an inert solvent such as an ether or a hydrocarbyl hydrocarbon, for example. Diethyl ether, tetrahydrofuran or methylene chloride, or in a mixture thereof, if necessary, in the presence of a base such as an organic base, for example a, preferably sterically hindered, tri-lower alkylamine, eg Ν, Ν-diisopropyl-N-ethyl-amine, and with cooling, at room temperature or under slight heating, for example at about -20 ° C to about 5O ⁰ C, if necessary in a closed vessel and / or in an inert gas, for example nitrogen atmosphere.

Further suitable etherifying agents are finally corresponding 1-substituted-3-aryl triazene compounds in which the substituent is the etherifying radical and aryl is preferably optionally substituted phenyl, for example lower alkylphenyl, such as 4-methylphenyl. Such triazene compounds are 3-aryl-1-lower alkyl triazenes, eg 3- (4-methylphenyl) -1-methyl-triazene, 3- (4-methylphenyl) -1-ethyl-triazene or 3- (4-methylphenyl) -1 isopropyl-triazene. These reagents are usually in the presence of inert solvents, such as optionally halogenated hydrocarbons or ethers, for example benzene, or solvent mixtures, and with cooling, at room temperature and preferably at elevated temperature, for example at about 2O ⁰ C to about 100 ⁰ C, if necessary in a closed vessel and / or in an inert gas, eg nitrogen atmosphere used.

- 45 -

The conversion of free carboxyl in a compound of formula (I) into esterified carboxyl may be further effected, for example, by reacting a compound of formula (i) wherein other optional functional groups are optionally in protected form or a reactive functional carboxy derivative , including a salt thereof, with an appropriate alcohol or a reactive functional derivative thereof.

The esterification of free carboxyl with the desired alcohol is carried out in the presence of a suitable condensing agent. Common condensing agents are e.g. Carbodiimides, for example Ν, Ν'-diethyl, N, N'-dipropyl, Ν, Ν'-dicyclohexyl or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or 1 , 2-oxazolium compounds, ζ B. 2-ethyl-5-phenyl-1,2-bxazolium-3'-sulfonate and, 2-tert-butyl-S-methyl-isoxazolium perchlorate, or a suitable acylaminoybean bond, eg 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline. The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, e.g. Methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran and, if necessary, carried out under cooling or heating and / or in an inert gas atmosphere.

Suitable reactive functional derivatives of the carboxyl compounds of formula (I) to be esterified are e.g. Anhydrides, especially mixed anhydrides and activated esters.

Mixed anhydrides are e.g. those with inorganic acids, such as hydrohalic acids, i. the corresponding acid halides, e.g. chlorides or bromides, also hydrazoic acids, i. the corresponding acid azides, as well as phosphorus-containing acids, e.g. Phosphoric acid, diethylphosphoric acid or phosphorous acid, or sulphurous acids, e.g. Sulfuric acid, or Cyanwasserstof.fsäure. Mixed anhydrides are further e.g. those

with organic carboxylic acids, 'as with optionally, for example by Halogeny such as fluorine or chlorine,', substituted lower alkanecarboxylic acids such as pivalic or. Trichloroacetic acid, or with half esters, in particular lower alkyl semiesters. the carbonic acid, such as ethyl or Isobutylhalbestern the carbonic acid j, or with organic, especially aliphatic or aromatic aromatic sulfonic acids, for example p-toluenesulfonic acid :. ·. '.' , V- "'.- .. ·'""..';'.''; - ''.''" - Ί ^/:. ' ^: ..--.'^;' ^: ..' · >

For reaction with an alcohol suitable activated esters of a Ver; Compounds of the formula I with at least one carboxyl group are, for example, esters with vinylogues; Alcohols (ie enols), such as virallogeneic lower alkenols, or iminomethyl diester halides, such as dimethyliminomethyl ester chloride (prepared from the carboxylic acid and dimethylchloromethylidene-iminium chloride of the formula [(CH ₃ ) N = CHCl] ⁺ Cl ;, or aryl esters, such as Pentachlorophenyl, 4-nitrophenyl or 2,3-dinitrophenylescer, heteroaromatic isomers, such as benzotriazole, eg 1-benztriazole, or diacylimino esters, such as .succinylimino or phthalylimino esters.

The reaction between such an acid derivative of the formula I, such as an anhydride, in particular an acid halide, and an alcohol is preferably carried out in the presence of an acid-binding agent, for example an organic base, such as; an organic amine, e.g. a tertiary amine such as tri-lower alkylamine, e.g. Trimethylamine, triethylamine or ethyldiisopropylamine, or Ν, Ν-di-lower alkylaniline, e.g. Ν, Ν-dimethylaniline, or a cyclic tertiary amine, such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a pyridine-type base, e.g. Pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonates or bicarbonate, e.g. Sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide, or propylene oxide.

. ':   -: '.' ·. · '.' '' '¹V-. ' '.: *. · '

A reactive functional derivative of the esterifying alcohol is, in the first place, a corresponding ester, preferably with a strong inorganic or organic acid, and in particular forms a corresponding halide, e.g. Chloride, bromide or iodide, or a corresponding lower alkyl or aryl, such as methyl or A-methylphenylsulfoquyloxy compound. , , :

Such a reactive ester of an alcohol can be reacted with the free: carboxyl compound of the formula (I) or a salt such as an alkali metal or aminonium salt thereof, preferably using the acid in the presence of an acid-binding agent.

The above esterification reactions are carried out in an inert, usually anhydrous solvent or solvent mixture, for example in a carboxamide, such as a formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, an ester, for example ethyl acetate, or a nitrile, zBAcetonitril, or mixtures thereof, if necessary with cooling or warming, for example in a temperature range of about -40 ⁰ C to about +100 ⁰ C, preferably at about -10 ⁰ C to about +40 ⁰ C, Uncl / drunk, he in an inert gas, eg nitrogen atmosphere.

Further, if desired, the acid derivative may be formed in situ . Thus, for example, a mixed anhydride is obtained by treating the carboxylic acid compound with appropriately protected functional groups or a suitable salt thereof, such as an ammonium salt, for example with an organic amine, such as piperidine or 4-methylmorpholine, or a metal, eg., Alkali metal salt with a suitable Acid derivative, such as the corresponding acid halide of an optionally substituted lower alkanecarboxylic acid, eg trichloroacetyl chloride, with a half ester of a carbonic acid halide, eg chloroformate or isobutyl ester, or with a halide of a di-lower alkyl phosphoric acid, eg diethyl

; , - 48 .-. , .... ·. . '; . '^; , ^: .. : " ^: ; ^: ;

phosphorus bromide, and uses the thus obtained mixed anhydride without isolation. /; ^:

For the esterification (acylation) of a hydroxy group in a compound of the formula I, the starting material of the formula (I) is treated with an acylating agent which introduces the desired ethenyl radical of an organic carboxylic acid. In this case, the corresponding carboxylic acid or a reactive derivative thereof, in particular an anhydride, including a mixed or internal anhydride of such an acid is used. Mixed anhydrides are Z ^ B. those with hydrogen halides, ie the corresponding acid halides, in particular chlorides, also with; Hydrocyanic acid, or then those with; suitable carbonic acid half derivatives, such as corresponding half esters (such as the mixed anhydrides formed, for example, with a halo-formic acid-lower alkyl, such as ethyl or isobutyl chloroformate, or with unsubstituted, substituted, for example halogen, such as chlorine, containing Niederaikancärbonsäuren ( such as the mixed anhydrides formed with pivaloyl chloride or trichloroacetic acid chloride). Internal anhydrides are, for example, those of organic carboxylic acids, ie ketenes, such as ketene or diketene, or those of carbamic or thiocarbamic acids, ie isocyanates or isothiocyanates. Other reactive derivatives of organic carboxylic acids useful as acylating agents are activated esters such as suitably substituted lower alkyl, eg cyanomethyl, or suitably substituted phenyl, eg pentachlorophenyl or 4-nitrophenyl esters. The esterification may, if necessary, in.Gegenwart of suitable condensation agents, with the use of free carboxylic acids, for example in the presence of carbodiimide compounds such as dicyclohexylcarbodiimide, or carbonyl compounds ^such: as Diitnidazolylcarbonyl, and when using reactive acid derivatives, for example in the presence of basic agents, such as Triniederalkylaminen, eg triethylamine, or heterocyclic bases, such as pyridine, are performed. The acylation reaction can be carried out in the absence or in the presence of a solvent or solvent mixture, with cooling, at room *

· '. "'.' · ^: '' - '.''"''' ·. '" ⁴⁹ ' - '"''- ^ ¹ - ': ' ^: . ^: '-. '''''''

temperature or with heating, and if necessary in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere, are performed. Suitable solvents are e.g. optionally substituted, especially optionally chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as benzene or toluene, it also being possible to use suitable esterification reagents, such as acetic anhydride, as diluents.

One by an organic sulfonic acid, e.g. Lower alkanesulfonic acid, such as methanesulfonic acid, or an aromatic sulfonic acid, such as p-toluenesulfonic acid, esterified hydroxy group may preferably be prepared by treating the starting material of formula (i) with a reactive sulfonic acid derivative, such as a corresponding halide, e.g. Chloride, if necessary, in the presence of an acid-neutralizing basic agent, e.g. an inorganic or organic base, e.g. in an analogous manner as the corresponding esters with organic carboxylic acids.

In a compound of the formula I which has at least one carboxyl group or a reactive derivative thereof, this can be amidated analogously to the method of d) for the acids of XII or their acid derivatives. Described with an amiri.

The starting materials required to carry out the processes a) to i) described above are known or can be prepared by methods known per se> ζ; B .. according to or analogous to those described in this application. '

Functional groups in starting materials can be protected with the same protective groups as mentioned for corresponding functional groups in the end-products of the formula I in this application. The introduction and removal of these protective groups can also be carried out in the manner described in the cited references. '. '-', "·" - ,, -. 'Λ:' "· -: ·". '.- · .-' '. , '

- 50 -

In a resulting compound of formula (I) wherein one or more groups are protected, these funktiohelle> for example, can be protected carboxyl, and / or HydTöxygruppen, in on / off manner known per se, by means of SoIvolyse; in particular hydrolysis, alcoholysis or acidolysis, or, in some cases, by careful reduction, if necessary, in stages or simultaneously. Saiylsciiutzgruppen / are-votteilhafterweise. ·· with fluorides, such as tetraethylammonium flupride cleaved.

:. Salts Of compounds of formula (I) having salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of formula (I) with acidic groups, e.g. by: treating with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. your sodium salt of a-ethyl caproic acid, or with inorganic alkali or alkaline earth metal salts, e.g. Sodium bicarbonate, or form with ammonia or, a suitable organic amine, which amounts to stoichiometric amounts or use only a small excess of the salt-forming agent. det. Acid addition salts of compounds of formula (I) with at least one basic group, e.g. a free amino group, is obtained in a conventional manner, z, B. by treating with an acid or a suitable aniorium exchange reagent. Internal salts of compounds of formula (I) which are e.g. a free carboxyl group and a free amino group may e.g. by neutralizing salts, such as acid addition salts, to the ispelectric point, z <B. with weak bases, or by treatment with liquid ion exchangers. , . ' "".

Salts can be converted in the usual way in the free compounds

:. , , , '':. , '''/, metal and ammonium salts, for example by treatment with suitable acids, and acid addition salts, for example by treatment with a suitable basic agent.

- 51 -

Mixtures of isomers may be prepared in a manner known per se, e.g. fractionated crystallization, chromatography etc. are separated into the individual isomers.

Racemates can be prepared in a manner known per se, e.g. after conversion of the optical antipodes into diastereomers, for example by reaction with optically active acids or bases, are cleaved.

The Erfindung.betrifft also to those forms of the process in which ^ man "from a receive escape at any stage as well. Intermediate Verbinduhg starts and carries out the missing steps, or ^ to .abbricht the method on any. .O4eX- stage ⁱⁱ ^ n'yelh 'a \ riäc.h \ .d $ ^fe; Ne - irfihdungsgemässeri method available compound produced under the process conditions and in situ wei't: erverarbeite.t νΛ - / ^ί': - '. · · · ^Ν ν '.. ·: · ^Λ::: '> ^: - / '>.'''^; ... .. '''

^! Novel starting materials and / or intermediates as well as processes for their preparation are also the subject of the present invention. Preference is given to using such starting materials and selecting the reaction conditions such that compounds which are particularly preferred are listed in this application reaches ^

The pharmacologically useful compounds of the present invention may e.g. for the preparation of pharmaceutical preparations which contain an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients.

The pharmaceutical preparations according to the invention are those for enteral, such as oral or rectal as well as parenteral, such as intraperitoneal, intramuscular or intravenous administration to warm-blooded animals, which contain the pharmacological active ingredient alone or together with a pharmaceutically acceptable carrier material.

- 52 -

The dosage of the active ingredient depends on the species of warm-blooded animals, the body weight, age and the individual condition, the disease to be treated as well as on the method of application.

The dosage is between about 0.1 and about 100 mg / kg daily. preferably / between about 0.1 and about 40 mg / kg daily, eg at about 10 mg / kg daily. , '; V _{: (} .. .. ..

Those on warm-blooded animals, e.g. Human doses of about 70 kg body weight are between about 10 rags and about 10 g, preferably between about 100 mg and 2 g, e.g. at 600 mg, per warm-blooded animal per day, distributed up to about 12, preferably 2 to 4, e.g. 3, single doses, e.g. can be the same size. The dosage in enteral and parenteral administration is substantially the same. The dependence of the dosage on the body weight is not linear, but γ is rather weak, so that the above-mentioned dosage is also used in warm-blooded animals of lower or higher body weight than 70 kg, e.g. 35 kg or 100 kg., Can apply. Usually, however, children receive half the adult's disease.

The novel pharmaceutical compositions contain a significant amount, especially from about 1% to about 99%, mainly from about 10% to about 95%, preferably from about 20% to about 90% of the active ingredient. Invention Pharmaceutical preparations can be used e.g. in the form of tablets, such as dragees, tablets, capsules, suppositories or ampoules.

The pharmaceutical preparations of the present invention are prepared in a manner known per se, e.g. by conventional mixing, granulation, coating, solution or Lyophiliöierungsverfahren produced. Pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained and mixing the mixture or

; .:.: '. , , , _; -. , -.53- -. , ''',; - ... '. , _: .-. /; ../^:- ' ^:

Granules, if desired or necessary after addition of suitable excipients, processed into tablets or dragee cores. They can also be incorporated into plastic carriers, which deliver the active ingredients dosed or diffused.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphospholate, furthermore binders , such as starch pastes using, for example, maize, wheat or clover or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl-methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, dispersing agents such as the pillared starches, furthermore carbdxymethyl starch, cross-hatched polyvinyl pyrrolidone, agar, alginic acid or a salt such as Natriutnalginat. Auxiliaries are in the first place flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate. : and / ode.r Pplyäthylenglykpl. Dragee kernels are provided with suitable, optionally enteric coatings, wherein! concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable prganic solvents or solvent mixtures, or for the manufacture of enteric coatings, solutions of suitable cellulose preparations, such as Acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The Tabiettert or dragee coatings may contain dyes or pigments, for example for identifying or labeling different doses of active substance. ¹

The preparation of the injection preparations takes place in

Usually under ant imikrobiel len conditions, as well as the filling in ampoules or vials and the closure of the container.

'Γ. ','''.'~ ⁵⁴ ~' · '.'. ''''. , '': /;

To prepare the injectable preparations, it is preferable to use solutions of the active ingredient, as well as suspensions, in particular isotonic aqueous solutions or suspensions, these being e.g. for lyophilized preparations containing the active substance alone or together with a carrier material, e.g. Mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure uride / pder the buffer and are prepared in a manner known per se, e.g. using co-solvents or lyophilization reagents. The solutions or suspensions mentioned may be viscous-susceptible substances, such as sodium. , Carboxymethylcellulose ^ Garboxyinethylcellulöse, dextran, polyvinyl pyrrolidone or gelatin ι contain ^ ^

Exporting Examples ... ';;

The following examples illustrate the invention. Temperatures are given in degrees Centigrade. R values are determined on silica gel thin-layer plates (Merck, Darmstadt, Germany) unless otherwise stated.

EXAMPLE 1 36 g (0.088 mol) of 2- (4-hydroxy-2-oxo-1-pyrrolidinyl) -acetic acid-pentachlorophenyl ester and 14.7 g (0.088 mol) of glycyl-glycinamide hydrochloride are stirred into 250 ml of dimethylformamide and mixed with 13 ml ( 0.088 mol) of triethylamine. The suspension is stirred for 20, hours at room temperature and then sucked off. The clear filtrate is stirred with 1.5 liters of ethyl ether, whereupon an OeI precipitates, which crystallizes after stirring for one hour. The crystals are aspirated off, dissolved in 100 ml of water and then passed through a 400 ^x g column of Amberlite IR 120 (H-formic acid cation exchanger). The aqueous eluate is evaporated on a rotary evaporator (6O ° / 12 min.) The semi-solid residue is hot in 300 ml of ethanol, filtered and ice bath; let crystallize. ; -:

The crude product, ^ em ^ melting point 133 ° r9 is again crystallized from ethanol, aspirated and getrocknfet at 12O ⁰ ZLZ Torr in a desiccator, whereupon ·; N - [(4-hydroxy-l ⁱ -2röxo-pyrrolidiny 1) acetyl] -glycyl - ^ glyGinamid receives 141 °, m.p. 135 ^.

fc ^ a, 0, (272,26) - Calc .: C 44,15 H 5,93 N 20,58

The as. Starting product used ester obtained as follows:

4.0 g (0.034 mol) of 4-amirio-3-hydroxybutyric acid are melted at 200-250.degree. C. The billet is distilled in a bulb tube at 18.degree. C., 0.02 Torr. '· ..; ';. _^"';.; '';'.'''''''

The distillate is dissolved in ethanol hot, cooled and treated with ethyl ether. The resulting crystals of 4-hydroxy-2-oxopyrrolidine are filtered off and washed with ethyl ether, after which they melt at 118-120 °.

- 56 · -.

I ₅ Og (0.01 mol) of 4-hydroxy-2-oxopyrrolidine and 1.1 g of 0.015 mol of ethyl vinyl ether in 6 ml of chloroform are stirred at room temperature. To this suspension is added a small spatula tip (about 30 mg) of trichloroacetic acid. The suspension is heated for 10 minutes at 50 ⁰ C, whereupon a clear solution is formed, which is stirred at room temperature for 18 hours. . '''>.'''.' ... ·. ·; -. ", ... · ';

The reaction mixture is extracted with 10 ml of saturated aqueous sodium bicarbonate solution. The chloroform phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated by evaporation in a kugelrohr and then 4- (1-ethoxyethoxy) -2-oxopyrrolidine as clear, colorless oil with R = 0.40 (toluene: ethanol = 8: 2; silica gel).

1.1 g (0.0064 mol) of 4- (i-ethoxyethoxy) -2-oxo-pp: rolidine in 10 ml of toluene and 0.3 g of a 50% suspension of sodium hydride in mineral oil are incubated for one hour at room temperature touched. Then added dropwise with cooling in an ice bath and stirring within 10 minutes, a solution of 2.5 g (0.0064 mol) of Bromessigsäurepentachlorophenylester in 5 ml of toluene. The reaction mixture is stirred for 18 hours at room temperature. The brownish suspension is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated at 65 ° -V12 Torr, whereupon a viscous OeI is obtained, which is mixed with 20 ml of methanol and filtered. \

The filtrate containing 2- [4- (l-ethoxy-ethoxy) ^ 2-oxo-l-pyrrolidinyl] -acetic acid pentachlorophenyl ester is added with 0.2 g of p-toluenesulfonic acid monohydrate and allowed to stand for 30 minutes at Rapmtemperatur , It is then evaporated and the resulting solid is boiled with hexane to free the mineral oil. The insoluble in hexane portion is recrystallized from ethyl acetate to give 2- (4-hydroxy, 2-oxo-l-pyrrolidinyl) -acetic acid-pentachlorophenylester having a melting point of 182-186 °. <

The bromoacetic acid ester used is obtained as follows:

14.0 g (0.1 mol) of bromoacetic acid and 32 g (0.12 mol) of pentachlorophenol are dissolved in 250 ml of absolute tetrahydrofuran. The yellowish solution is stirred in an ice bath and treated dropwise with a solution of 22.7 g (0.11 mol) of dicyclohexylcarbodiimide in 75 ml of absolute tetrahydrofuran, wherein the temperature is kept below 10 °. Then it is stirred for one more hour in an ice bath and 2 ° hours at room temperature.

The precipitated dicyclohexylurea is filtered off with suction and the filtrate concentrated at 6OV12 Torr. The residue is dissolved in 500 ml of ethyl ether and filtered. The clear filtrate is extracted with 50 ml of cold 1N sodium hydroxide solution, washed with sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The solid residue is recrystallized from hexane to give: bromoacetic acid pentachlorophenyl ester of melting point 113-115 °.

C ₀ H ₀ Cl ₁ -BrO. (387 * 27) Ber. C, 24.81, H, 0.52,

OZ J.. Z. , , '':::; ..-

Gef. C 25.1 H 0.7

I. ':. ^: . .. · '. ,

Example 2; 9.0 g (0.04 mol) of glycyl-glycyl-glycinamide hydrochloride and 9.6 g (0.04 mol) of 2- (2-oxo-1-pyrrolidinyl) -acetic acid N-hydroxy-succinimide ester are dissolved in 400.degree stirred into absolute DMF and treated with 1 ml of triethylamine. The reaction mixture is stirred at room temperature for 24 hours. Most of DMF is removed by rotary evaporation at 12 torr and 70 °. The residue is suspended in absolute ethanol and filtered with suction. The product obtained is dissolved in 100 ml of water to remove triethylammonium chloride and washed through a column with 60 ml of Aberlite IR-120 (strong acid cation exchanger, H form). The aqueous eluate is evaporated on a rotary evaporator, dissolved in 20-22 ml of water, with 100 ml.

- 58 -. '. ^; -:

Ethanol and placed in a refrigerator (5 °). The resulting colorless crystals of N - [(2-oxo-1-pyrrolidirinyl) -acetyl] -glycyl-glycyl-glycinamide have a melting point of 230-232 ° C. after aspiration and removal of the solvent at 8 ° Torr.

C ₁₂ H ₁₉ N ₅ O ₅ (313.31) Calc. C 45.98 H 6.11 N 22.36. Gef. C 45.6 H 5.9 N 22.2

The starting materials used are obtained as follows:

A solution of 14 g (0.08 mol) of N-tert-butyloxycarbonyl-glycine (obtained from Fluka) in 240 ml of DMF is first admixed with 22 ml (0.16 mol) of triethylamine, followed by 10.4 ml of 0.08 mol) of isobutyl chloroformate. After stirring for 30 minutes at Raumr temperature is added 13.4 g (0.08 mol) of solid glycyl-glycine hemide hydrochloride and 10.4 ml (0.08 mol) of triethylamine and stirred for 18 hours at room temperature. The solution is acidified with 6 normal alcoholic hydrochloric acid until the color change of the indicator Congo red and concentrated on a rotary evaporator at 6OV12 Torr. The residue is boiled up in 300 ml of ethanol and the solid contained in it is filtered off with suction, the solid is dissolved in 400 ml of water, the solution is filtered, diluted with 1000 ml of ethanol and placed in a refrigerator. The precipitated crystals of glycyl-glycyl-glycine hemide 'hydrochloride have a melting point of 240-243 ° after suction and removal of the solvent at IOOV12 Torr.

C ₆ H ₁₂ N ₄ O ₃ .HCl (224.65) Ber. C 32.08 H 5.83 N 24.94

Gef. C 32.0 H 6.0 N 24.8

To a suspension of 25.6 g (0.18 mol) of 2- (2-oxo-1-pyrrolidinyl) -acetic acid and 20.6 g (0.18 mol) of N-hydroxysuccinimide in 450 ml of dioxane are added 37.6 g (0.18 mol) dicyclohexylcarbodiimide in portions with cooling with ice water stirred. The mixture is then stirred for 18 hours at room temperature and sucks the precipitated dicyclohexylurea

- 59 -

from. The filtrate is concentrated on a rotary evaporator at 6OVl2 Torr. The residue is crystallized from ethyl acetate / diethyl ether. The resulting 2- (2-oxo-1-pyrrolidinyl) -acetic acid N-hydroxy-succinimide ester melts at 128-130 °.

C HJO (240,22) Ber. C 50.00 H 5.04 N 11.66 * V Gef. C 49.9 H 5.2 N 11.8

Example 3: 6.6 g (0.02 mol) of 2- (4- [4-fluoro-phenyl] -2-oxo-1-pyrrolidinyl) -acetic acid N-hydroxysuccinimide ester and 3.35 g (0.02 mol ) Glycylglycinamid hydrochloride are stirred into 400 ml of absolute DMF, after which 6.11 ml of triethylamine within 10 min. With stirring let flow. The suspension is stirred for 20 hours at room temperature and then concentrated in vacuo (water jet pump). The yellowish solid residue is stirred with 200 ml water, cooled in ice-water bath and filtered with suction ^r. The still moist colorless filter residue is dissolved in 140 ml of water at 90 °. The solution is filtered and placed in an ice-bath, whereupon N - ((4- [4-fluoro-phenyl) -2-oxo-1-pyrrolidinyl-D-acetyl-glycyl-glycineamide, mp 200-202 ° crystallizes out.

C ₁₆ H ₁₉ N ₄ O ₄ (350.35) Calc. C 54.9 H 5.50 N 16.0

Gef. C 55.3 H 5.6 N 16.0

The starting materials used are obtained as follows:

To a solution of 35.6 g (0.15 mol) of 2- (4- [4-fluoro-phenyl] -2-oxo-1-pyrrolidinyl) -acetic acid and 17.25 g (0.15 mol) of N-hydroxysuccinimide in 570 ml of dioxane is stirred in portions within 10 minutes 31.5 g Dicyclohexylcarbödiimid, keeping the reaction temperature by cooling with ice water below 30 °. After 18 hours of stirring at room temperature, the resulting dicyclohexylurea is filtered off with suction and the clear filtrate is evaporated to dryness. The oily residue is taken up in 200 ml of ethyl acetate and hexane is added to turbidity, whereupon colorless 4- (4-fluoro-phenyl) -2-oxo-pyrrolidi T nyl ^ acetic acid N-hydroxysuccinimide ester with melting point 120-123 °

crystallized. :

Example 4 4.4 g of triethylamine are added with stirring to a solution of 4.9 g (0.031 mol) of 5-methyl-2-oxopyrrolidinylacetic acid in 75 ml of DMF (purissimum) at 10 °. It is cooled to -15 ° and added dropwise with stirring 4.23 g (0.031 mol) of isobutyl chloroformate. After stirring for 20 minutes, 5.2 g (0.034 mol) of glycylglycinamide hydrochloride and then 4.4 ml (0.035 mol) of triethylamine are initially added at -10 °. The mixture is stirred for one hour at 0-5 ° and 22 hours at 20 ° to form a suspension. The reaction solution is diluted with 250 ml of ether and the crystalline crude product is filtered off with suction, which is then stirred in 120 ml of absolute ethanol to wash out triethylammonium chloride. It is sucked off, washed with diethyl ether, the filter residue in 200 ml of methanol in the heat, the previously filtered solution is concentrated to 50 ml, filtered off with suction, washed with ethanol and ether and dried as filter residue N- [(5- Methyl-2-oxo-1-pyrrolidirinyl-acetyl-glycyl-glycinamide having a melting point of 197-198 ° C. "" , "" , .

Ό, .Η, βΝ.Ο. (270,29) Ber. C 48.88 H 6.71 N 20.73

11 Ιο HM-

Gef. C 49.18 H 6.44 N 20.96

Example 5 ; 6.0 g (0.042 mol) of 2-oxopyrrolidinylacetic acid and 5.3 ml (0.042 mol) of N-ethylmorpholine are dissolved in 100 ml of dimethylformamide and treated at -15 ° with 5.5 ml (0.042 mol) of isobutyl chloroformate. After 10 min. At -15 ° is added dropwise a solution of 7.8 g (0.051 mol) of glycyl-alaninamide hydrochloride and 5.3 ml of N-ethylmorpholine in 200 ml of dimethylformamide in such a way that the temperature never exceeds -10 °. After a further hour at -10 ° and 10 hours at 2.0 °, the reaction mixture is evaporated, the residue taken up in water and passed through a column of strongly basic ion

exchanger (in free form, ie with free dialkylamino groups, Merck III). The eluate is evaporated and the residue is recrystallized from methanol-ether, whereupon N- [(2-oxo-1-pyrrolidinyl) acetyl] -glycyl- (L) -alanineamide with melting point 196-198 °, [α] ²⁰ = -22 ° (c - 1.204, water) and R _f = 0.40 (solvent system A, ie n-butenol / pyridine / acetic acid / water = 42/24/4/30).

Analogously you get:

N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl * - (D) -alaftineamide with mp 195-196 °, [α] _D ° = + 24 ° (c = 0.873, water) and R _f - 0.40. (System A),

N- [(2-0x: ol * -pyrrolidinyl) acetyl] -glycyl- (L) -alanine-1-N-ethyl-amide with melting point 195-196% [a] _ = -35 ° (c = 0.858, Water) and R = 0.48

(System A), / '

N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl ^ (D) -alanine * N-ethyl-amide of melting point 202-203 °, [α] ° = + 38 ° (c = 0.916, Water) and R _f = 0.48 (system A), as well

N - [(2 ⁱ -0xo-l-pyrroiidinyl) acetyl] -glycyl (L) -alanine-N, N-diethy1-amide and · · .. ', · -. · · · · · ·. ".".

N - [(2-Oxol-1-pyrrolidinyl) -acetyl] -glycyl- (D) -alanine-N, N-diethyl-amide, both as OeI and with R = 0.52 (System A).

The peptide glycyl (L) -alaninamide hydrochloride used as the starting substance is treated as follows:

To 13.51 g (0.065 mol) of N-benzyloxycarbonylglycine, 8.0 g (0.0645 mol) of alanineamide hydrochloride and 8.15 ml (0.068 mol) of N-ethylmorpholine in • 200 ml of dimethylformamide are added at 0 ° 14, 65 g (0.071 mol) of dicyclohexylcarbodiimide and 10.88 g (0.08 mol) of 1-hydroxybenzotriazole. After 15 hours at 20 °, the filtrate is evaporated, the residue is taken up in ethyl acetate and this solution is washed with 0.5 normal aqueous citric acid solution, 0.5 normal aqueous sodium bicarbonate solution and water, the organic phase is dried over sodium sulfate and evaporated. After recrystallization of the residue

- 62 -

Methano1 / ether gives N-benzyloxycarbonyl-glycyl-CD-alaninamide with melting point 181-182 ° and, [a] = -10 ° (c = 0.781, methanol).

In an analogous manner one obtains:

N-? -Enzyloxycarbonyl-glycyl- (D) -alanineamide with melting point 182-183 ° and [a] p ° = + 12 ° (c = 1.283, methanol), ί N-benzyloxycarbonyl-glycyl- (L) -alanine-N ethyl amide with melting point 134-136 ° and [a] ^ = -27 ° (c = 1.126, methanol), N-benzyloxycarbonyl-glycyl- (D) -alanine-N-ethyl-amide with melting point 138-140 ° and [α] * = + 29 ° (c - 0.896, methanol),

N-benzyloxycarbonyl-glycyl-C 1-4 -alanine-N, N-diethyl-amide of melting point 92-93 ° and [a] = = -9 ° (c = 1.627, chloroform) and N-benzyloxycarbonyloyl-glycyl (D) -alanine-N , N-diethyl-aniide with melting point

'' 70 ·. '·'

90-92 ° and [a] ^ = + 9 ° (c = 1.724, chloroform).,

A solution of 11.7 g (0.042 mol) of N-benzyloxycarbonyl-glycyl-alanineamide in 400 ml of methanol and 41.9 ml of 1.0 normal hydrochloric acid is hydrogenated in the presence of 1.2 g of precipitated carbon (10% Pd) at 22V84O Torr, wherein the resulting C0 "is absorbed in a second hydrogenation vessel with Inormal aqueous potassium hydroxide solution. After completion of hydrogen absorption (about 40 min.) Is filtered from the catalyst and the filtrate is evaporated.

In an analogous manner, the benzyloxycarbonyl protecting group is split off in the other abovementioned peptides.

The obtained glycyl-alaninamide hydrochlorides are used directly for the reaction described at the beginning of this example.

Example 6 : 4.4 g (0.011 mol) of 4- (4-chlorophenoxy) phenyl-2-oxopyrrolidinylacetic acid N, hydroxy-succinimide ester and 1.7 g (0.01 mol) of glycylglycinamide hydrochloride in 100 ml DMF are mixed with 2.8 ml

, \. :. '-..-. - 63 -. ... "; · · ·. /. ·;

Triethylamine and stirred for 20 hours at room temperature. The remaining after evaporation on a rotary evaporator solid residue is stirred with 50 ml of water at 50 °, filtered off with suction and washed with 10 ml of water. Bear solid filter residue, which melts after drying at 204-208 °, is boiled in 200 ml of water, allowed to stand at room temperature for 3 hours, filtered off with suction and dried.

C ₂₂ H ₂₃ ClN ₄ O ₄ (458.90) Calc. C 57.58 H 5.05 N 12.21

Gef. C 57.6 H 5.3 N 11.7;

The obtained N ~ {(4- [4-chlorophenoxy] -phenyl-2-oko-1-pyrrolidinyl) -acetyljr-glycyl-glycinamide melts at 211-213 °.

The Succinimidester used as starting substance is obtained as follows:

38.5 g (0.111 mol) of 4- (4-chloro-phenyl) -phenyl-2-oxo-pyrrolidinylacetic acid, 12.7 g (0.111 mol) of N-hydoxy-succinimide and 25.1 g (0.122 mol) of dicyclohexylcarbodiimide 1500 ml of dioxane are stirred for 20 hours at room temperature. The dicyclohexylurea formed is filtered off with suction and the filtrate is evaporated to dryness. The amorphous solid residue is crystallized from ethyl acetate-diethyl ether. After filtering off with suction and drying, 4- (4-chloro-phenoxy) -phenyl-2-oxo is obtained ^; -pyrrolidinyl-acetic acid N-hydroxy-succinimide ester with melting point 132-134 °. , : - '. · '''/,."..:.",.'.;';'' -

₆ (442.86) Ber. C 59.7 H 4.3 M N 6.3 Found C 60.1 H 4.4 N 6.3

Example 7: 7.2 g (0.027 mol) of 2- (5,5-dimethyl-2-oxo-1-pyrrolidinyl) -acetic acid (2,5-dioxo-1-pyrrolidinyl) ester, 4.5 g ( 0.027 mol) of glycyl-glycinamide hydrochloride and 7 ml of triethylamine are stirred in 90 ml of absolute dimethylformamide for 48 hours at room temperature.

The precipitated triethylamine hydrochloride is filtered off with suction and the filtrate is evaporated at 7O ° / 14 Torr to dryness. The residue obtained as viscous OeI is chromatographed over 200 g of silica gel 60 (Merck A.G.). The desired substance is eluted with methanol, the eluate is evaporated and crystallized from ethanol-ether, whereupon N - [(5,5-dimethyl-2-oxo-1-pyrrolidinyl) -acetyl] -glycylglycinamid with melting point 138-140 ° receives ,

^C 12 ^H 2 O ^N 4 ° 4 < ²⁸⁴ » ³² >

Ber. C 50, 70 H 7 , 09 N 19 , 71 Gef. C 50, 5 H 7 , 0 N 19 3

The succinimide ester used as starting material is obtained

follow because wet:

27.8 g (0.162 mol) of 2- (5,5-dimethyl-2-oxo-1-pyrrolidinyl) -acetic acid and 18.6 (0.162 mol) of N-hydroxy-succinimide are dissolved in 400 ml of dioxane and taken up in portions with 34 g (0.162 mol) of Ν, Ν'-dicyclohexyl ^k carbodiimid added. The temperature is kept at 27-30 °. After stirring for 20 hours at room temperature, the resulting dicyclohexylurea is filtered off with suction. The filtrate is evaporated at 6O ° / 14 Torr. The yellow, viscous OeI obtained as residue is dissolved in 100 ml of ethyl acetate and admixed with 100 ml of ether. In the ice bath crystallized 2- (5,5-dimethyl-2-oxo-l-pyrrolidinyl) -acetic acid (2,5-dioxol-1-pyrrolidinyl) ester with a melting point of 100-105 °.

CH ₁₆ N 0 (268,27) Ber. C 53.73 H 6.01 ',

Gef. \ C 53,4 H 6,1

The starting material is obtained as follows:

53.2 g (0.287 mol) of 2- (5,5-l) imethyl-2-oxo-1-pyrrolidinyl) - 'acetic acid ethyl ether are with 19 g (0.287 mol) of 85 / iger aqueous potassium hydroxide solution in 300 ml of methanol for 2 hours under Reflux cooked. The reaction mixture is evaporated at 6O ° C / 14 Toirr to dryness. The residue is dissolved in 500 ml of water, adjusted to pH 4 with concentrated hydrochloric acid and evaporated. The residue is triturated in 200 ml of ethanol. It is suctioned off and the filtrate evaporated to dryness, dissolved in 100 ml of ethanol and diluted with 400 ml of ether. Upon standing in an ice bath, 2- (5,5-dimethyl-2-oxo-1-pyrrolidinyl) -acetic acid crystallizes with melting point 128-130 °.

^C 8 ^H 13 ^NO 3 (171 , 30) Ber. C 56 13 H 7 , 66 N 8th, 18 Gef. C 55 , 9 H 7 , 7 N 8th, 1

The starting material is obtained as follows:

From 11.5 g (0.5 gram atom) of sodium, a sodium methoxide solution is prepared with 350 ml of methanol. In this solution, 56.5 g (0.5 mol) of 5,5-dimethyl-2-pyrrolidone [Org. Synthesis IV, 357 (1963) 1 'stirred. After 3 hours, the reaction mixture is evaporated to dryness. The dry sodium salt of the pyrrolidone is suspended in 250 ml of toluene and treated dropwise with 53 ml of methyl bromoacetate in 50 ml of toluene . The suspension is stirred at room temperature for 20 hours.

The reaction mixture is extracted with 200 ml of water. The organic layer is dried over sodium sulfate, filtered and evaporated. The residue is fractionated in a high vacuum. The fraction with boiling point 1O4VO, OO5 Torr consists of 2- (5,5-dimethyl-2-oxo-l-pyrrolidinyl) -acetic acid ethyl ester.

C ₉ H ₁₅ NO ₃ (185.22) Ber. C 58.36 H 8.16 N 7.56

Gef. C 58.0 H 8.5 N 7.4

': ^6δ - "''^;'' ·. · '^; : ' : '- ^.

Example 8: A mixture of 14.6 g (0.04 mol) of 2- [4- (1-naphthyl) -2-oxo-1-pyrrolidinyl] -acetic acid (2,5-dioxo-1-pyrrolidinyl) - ester, 6.7 g (0.04 mol) of glycyl-glycine amide hydrochloride and 8.1 g (11 ml) of triethylamine in 150 ml of dimethylformamide is stirred at 5O ⁰ C for 20 hours. Most of the resulting triethylamine hydrochloride is filtered off with suction. The clear filtrate is evaporated at 7O ° / 14 Torr. The oily residue is stirred into 50 ml of water and allowed to stand for 20 hours at 5 ° C. The crystalline precipitate is filtered off with suction and recrystallized three times from dimethylformamide / ether, whereupon N ~ tt4- (1-naphthyl) -2-oxo-1-pyrrolidinyl] -acetyl-glycylglycine amide having a melting point of 206-208 ° is obtained.

^C 20 ^H 22 ^N 4 ° 4 ⁽³⁸² \ ⁴²⁾

Ber. C 62 82 H 5, 80 N 14 »65 Gef. C 62 3 H 5, 9 N 14 , 4

The succinimide ester used as the starting product is obtained as follows:

A mixture of 11.5 g (0.043 mol) of 2- [4- (1-naphthyl) -2-oxo-1-pyrrolidinyl] -acetic acid, 4.9 g (0.043 mol) of N-hydroxysuccinimide and 8.9 g (0.043 mol ) Dicyclohexylcarbodiimide are stirred in 200 ml of absolute dioxane at room temperature for 20 hours. ,

The precipitated dicyclohexylurea is filtered off with suction. The clear filtrate is evaporated to dryness at 6O ° / 14 torr followed by 2- [4- (1-naphthyl) -2-oxo-1-pyrrolidinyl] -acetic acid (2,5-dioxol-pyrrolidinyl) ester in the form of an oil which is used directly further. ^v .

The starting material is obtained as follows:

19.2 g (0.065 mol) of 2- [4- (1-naphthyl) -2-oxo-1-pyrrolidinyl] -acetic acid ethyl ester are dissolved in 100 ml of methanol and treated with 65 ml of aqueous 1 N sodium hydroxide solution. The mixture is stirred for 20 hours at room temperature and then evaporated to dryness at 60 ° / 14 torr. The residue is taken up in 100 ml of water and adjusted to pH 1 with 6N HCl. The precipitated ^ - [4- (i-naphthyl) -2-oxo-1-pyrrolidinyl] -acetic acid crystallizes in an ice bath and is

aspirated. , 7:. '.' , ·. '. , After recrystallization from 350 ml of methanol, it melts at 212-214 °. '. . ^ "· ^'..,';: - .. · ^';' C _1, H _{n, 0} NO (269.30) Calculated C 71.36 H 5.62 N 5.20....

Gef. C 71.2 H 5.6 N 5.1

The starting material is obtained as follows:

42.2 g (0.2 mol) of 4- (l-naphthyl) -2-oxo-pyrrolidine are dissolved in 300 ml of dimethylformamide and at room temperature with 8.8 g (0.2 mol) of a 55% suspension of Sodium hydride in mineral oil added * After completion of the addition is stirred for 2 hours at room temperature.

To this mixture, a solution of 22.4 ml (0.2 mol) of ethyl bromoacetate in 120 ml of toluene is added dropwise at 15 ° C within 20 minutes. The reaction mixture is stirred for 18 hours at room temperature and 8 hours at 80 °.

The reaction mixture is freed from toluene and dimethylformamide at 70 ° / 14 Torr. The oily residue is diluted with ethyl acetate and washed with saturated sodium chloride solution. After drying over sodium sulfate and evaporation, the oily residue is stirred twice with 50 ml of hexane to remove the mineral oil. The residue is distilled under high vacuum. The fraction at 190 ° / 0.005 Torr is a yellowish, clear OeI consisting of 2- [4- (1-naphthyl) -2-oxo-1-pyrrolidinyl] -acetic acid ethyl ester.

C ₁₈ H ₁₉ NO (297.35) Ber. C, 72.71 H, 6.44, N, 4.71

Ge _v f. '.''. C 72.4 H 6.7 N 4.8

• Example 9; In 300 ml of dry dimethylformamide 11.7 g (30 mmol) of 2- (2-0xo-l-pyrrolidiny]) - acetic acid-pentachlorphenylester and 10.2 g (30 mmol) of glycyl-glycyl-glycyl-glycyl-glycinamidhydrochlorid stirred and then added with 4.6 ml (33 mmol) of triethylamine. The suspension is heated 30 minutes at 70 ⁰ C intterthalb a UTID would stirred at this temperature. The white suspension is cooled to 10 ° and sucked off at 13 Torr. The

. '. '.' '.-' '68 - '' ':. '. '. .. ·.

Filtered material is washed with ethanol and ether and recrystallized twice from 300 ml of boiling water, whereupon N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl-glycyl-glycyl-glycyl-glycinamide having a decomposition range > 300 °.

C ₁ , H _0c N, 0, (427.42) Ber. C 44.96 H 5.90 N 22.94 Io 2.5 7 7 '. _:

C 44.6 H 5.8 N 22.6

The starting material is prepared as follows: To a solution of 23.2 g (0.1 mol) of N-tert-butyloxycarbonylglycyl-glycine with 14 ml of triethylamine in 700 ml of dimethylformamide at -10 ⁰ C 13.7 g (0, 1 mol) isobutyl chloroformate is added dropwise. After completion of the addition, stirring is continued for 10 minutes and then stirred at the unchanged temperature (-10 ⁰ C) 22.5 g (0.1 mol) of glycyl-glycyl-glycihamid hydrochloride. After addition of 14 ml of triethylamine was slowly warmed to room temperature and then stirred for 18 hours at 40 ^{0 C.;}

To cleave the protective group is then added 20 ml of 21% ethanolic hydrochloric acid solution and 1 ml of water and stirred for 1 hour at 40 ⁰ C. The reaction mixture is evaporated at 7O ° / 14 Torr to dryness. The residue is boiled in 600 ml of ethanol and filtered off with suction while hot. The filter residue is dissolved in 250 ml of water

''. '' '·'

heated. Aqueous 2 N hydrochloric acid is added to the base point of the indicator Kongoblau (pH <4), treated with activated charcoal and the filtrate is mixed with 700 ml of ethanol. In the ice bath, glycyl-glycyl-glycyl-glycyl-glycinamide hydrochloride crystallizes with a decomposition range of ^ 300 °

^C 10 ^H 18 ^N 6 ° 5 ^{# HC1} ( ³³⁸ » ⁷⁵ ) ^Ber · C 35.46 H 5.65 N 24.81

Gef. C 35.6 H 5.8 N 24.4

Example 10: A mixture of 5.6 g (0.02 mol), glycylglycylglycerylglycidamide hydrochloride, 3.1 ml (0.022 mol) of triethylamine and 11.7 g (0.02 mol) of 2- (2- Oxo-l-pyrrolidinyl) -acetic acid Pentfachlorphenylester is in 400 ml of dimethylformamide under nitrogen atmosphere at

     , '··' .. ''. '- 69 ..-'. .: '· ·.' '. "·. ;

Stirred for 15 hours. The reaction mixture is cooled to 15 ° and filtered with suction. The crystalline mass on the filter is stirred with 96% ethanol, filtered off with suction and washed with ether. The filter residue is dissolved in 100 ml of water at 90 °. The slightly turbid solution is filtered and cooled slowly to room temperature. The precipitated product is filtered off with suction and washed with ethanol and ether, whereupon N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycylglycyl-glycyl-glycidiamide with decomposition range 268-272 ° is obtained.

(370 , 37) Ber. C 45 , 4 H 6 , 0 N 22 , 7 Gef. C 44 » ⁸ H 6 » ² N 22 , 7 Gef. C 45 ,1 H 5 , 7 N 22 , 4

The starting material is prepared as follows: In 700 ml of dimethylformamide 23.2 g (0.1 mol) of N-t-butyloxycarbonyl-glycyl-glycine eingerühtt.Die solution is cooled to -1O ⁰ C and (with 14 ml of 0.1 mole ) Triethylamine added. At -10 °, 13.7 g (0.1 mol) of isobutyl chloroformate are added dropwise. After stirring for 10 minutes, another 14 ml (0.1 mol) of triethylamine, and then 16.8 g (0.1 mol) of glycylglycinamide hydrochloride are added as a solid. The reaction mixture is allowed to stand at room temperature for 40 hours. stirred * Λ ; '''.' .... ^'..,: to deprotection of the turbid yellowish suspension is treated with 1 ml of water and adjusted with ethanolic hydrochloric acid (21% strength) to pH1. The reaction mixture is evaporated to dryness at 60 ° C / 14 torr. The solid obtained is dissolved in 200 ml of water at 80 °, treated with activated charcoal and filtered with suction. The clear filtrate is diluted with 700 ml of ethanol and stirred in an ice bath. The precipitated product is filtered off with suction, dissolved in 100 ml of water at 80 ° and the solution is mixed with 500 ml of ethanol. After sucking off and drying glycyl-glycyl-glycyl-glycinamide hydrochloride is obtained in crystalline form, which melts above 280 °.

(281.70) Ber. C 34.1 H 5.7 N 24 ^ 9 Gef. C 34.0 H 5.5 N 24.3

    - .. '-. - 70 - ^ '. *,. ·.

Example 11: 3.3 g (0.01 mol) of N-tert-butyloxycarbonyl-L-proly-1-glycylglyeinamide are stirred in 10 ml of 1N HCl for 2 hours at 80 °. The clear solution is evaporated at 7O ° / 13 Torr and evaporated twice with 50 ml of toluene. The residue is taken up in 60 ml of dimethylformamide, mixed with 3.91 g (10 mmol) of 2- (2-oxopyrrolidin-1-yl) -acetic acid pentachlorophenyl ester and 1.4 ml (10 mmol) of triethylamine. The reaction mixture is stirred at 50 ⁰ C for 20 hours and then evaporated to dryness at 7OV13 Torr. The viscous residue is stirred with 50 ml of ethyl acetate in the heat-Ver:. The ethyl acetate layer contains pentachlorophenol. The glassy residue is chromatographed on 100 g of silica gel (Kieselgel 60, 70-230 mesh, Merck AG). The fractions eluted with chloroform / methanol = 20/1 are combined. The crude product obtained after evaporation of the solvent is taken up in 25 ml of water and washed through a short column with 10 g of Dowex 50 (cation exchanger, H form). The aqueous eluate is evaporated to dryness, whereupon N - [(2-oxo-1-pyrrolidinyl) -acetyl] -L-prolyl-glycyl-glycinamide is obtained in the form of an amorphous solid.

C ₁₅ H ₂₃ N ₅ O ₅ (353.38) Calc. C 50.99 H, 6.56 N, 19.82

Gef. C 50.8 H 6.6 N 19.8

100 MHZi- ¹ H-NMR (dimethylsulfoxide-d,): <£ = 1.7-2.4 ^f (8H), 3.3-3.6 (4H), 3.8 (4H), 4.1 (2H), 4.35 (IH), 6.7 (IH), 6.95 (IH), 7.9 (IH) and 8.6 (IH)

The intermediate is prepared as follows: A mixture of 23.2 g (0.05 mol) of N-tert-butyloxycarbonyl-L-proline pentachlorophenyl ester (mp 113-115 °), 5.8 g (0.05 mol) of glycylglycine amide hydrochloride and 7 ml (0.05 mol) of triethylamine in 250 ml of dimethylformamide is stirred at 60 ° under nitrogen atmosphere. After stirring for 15 hours, the reaction mixture is concentrated at 7O ° / 13 Torr to 80 ml and stirred again for 20 hours at 80 °. After cooling to room temperature, the precipitated triethylamine hydrochloride is sucked off. The filtrate is evaporated to dryness at 70V. The resulting viscous oil is stirred with 100 ml of toluene and 100 ml of ether. After stirring for 90 minutes, a

obtained amorphous solid which is soluble in hot dioxane and is crystallized from dioxane / ethyl acetate / ether = 7/10 / lQ, whereupon N-tert-butyloxycarbonyl ^ L-prolyl-glycyl-glyainamide with a melting point of 171-172 °.

C ₁₄ H ₂₄ N ₄ O ₅ (32β, 37> calc. C 51.21 H 7 .37 N 17,, O 6.-.-. 'Gef. C 51.3 H 7.2 N 16.8

Example 12; In an analogous manner, as described in this application, gives N- [4-hydroxy-2- (2-oxö ^ l-pyrrolidinyl) -butyryl] -glycyl-glycinamide.

Example 13 ; Recipe for a tablet:.

N - [(2-0xo-i-pyrrolidinyl) ^J -acetyl-glyci- (L) -alaninamide 100 mg

Strength . '. , ' ^: . , - ^: ·,. ^: · Ν; 15 mg: polyvinylpyrrolidone 2 mg

Talcum, 6 mg; '; .

. '·'. . ''''"'.'.''''' i '''''^i; !!

Magnesium stearate; 1 mg I

Example 14; Preparation of 1000 tablets each containing 100 mg of N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl-glycyl-glycinamide

Composition . ;, _.

N - [(2-oxo-1-pyrrolidinyl) -acetyl] -glycyl-glycyl-glycinamide 100 g

, , , ^ '' ⁽ - ^ '. Lactose I 100g

Potato starch 70 g

Gelatine L '!> 6 g

^Talk; '. '. ^:: ''. '. "· '';. '.' /. · '-Ι? G'

Magnesium steatate 2g

Silica (fumed) 4 g

Ethanol q.s.

The active ingredient is mixed with the lactose and 60 g of potato starch, the mixture is moistened with an alcoholic solution of gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the talc, the magnesium stearate and the finely divided silicon dioxide are mixed together and the mixture is compressed to 289.6 mg tablets of the abovementioned active ingredient content, which if desired may be provided with partial scores for finer adjustment of the dosage can. ,

Example 15 ; 20.7 g (0.1 mol) of 2- (5,5-dimethyl-2-oxo-1-pyrrolidinyl) -propionic acid sodium salt (described in German Offenlegungsschrift 27 47 369) and 16.8 g (0 , 1 mole) of glycyl-glycinamide hydrochloride are stirred in 150 ml of dimethylformamide for 10 minutes and then 32 ₍ 1 g (0.105 mol) of triphenyl phosphite added, then under nitrogen atmosphere and stirring for 2 l / l hours to 90-95 The mixture is cooled to 5 ° C. and treated with 300 ml of diethyl ether The precipitated crude product is filtered off with suction, warmed in isopropanol, freed from insoluble inorganic salts by filtration and then concentrated to incipient crystallization crystallized N- ^ 2- (5,5-dimethyl-2-oxo-l-pyrrolidinyl) -propionylj-glycyl-glycinamide is filtered off with suction and dried in vacuo at 80 °, mp 218-220 °.

Example 16 ; 3.17 g (0.01 mol) of NO-carboxy-propyD-glycyl-L-prolylglycyl-glycinamide are suspended in 25 ml of hexamethyldisilazane and heated to boiling with stirring. After a short time , a clear solution is formed. The mixture is refluxed for 24 hours and then the crude reaction mixture is evaporated under high vacuum. The residue is dissolved in 30 ml of methanol and stirred at room temperature. The precipitated, described in Example 11 N- * £ (2-0xo-lpyrrolidinyD-acetyl-L-prolyl-glycyl-glycinamide is filtered off with suction and washed with a little cold methanol.

    , ·; ·; .-. "73 - '. ·. ·. - ...;

The starting material is prepared as follows:

10.3 g (0.10 mol) of 4-amino-butyric acid, 28 g (0.20 mol) of potassium carbonate and 17.2 g (0.05 mol) of N-bromoacetyl-L-prolyl-'glycyl-glycinamide are in 300 ml of ethanol for 8 hours at 50 °

 This is carefully neutralized with 2N hydrochloric acid and then evaporated in a water-jet vacuum. The residue is treated with 250 ml of isopropanol and heated to boiling. The insoluble salts are filtered off with suction and the filtrate is concentrated on a rotary evaporator until incipient crystallization. Mari thus obtains the crude N- (3-carboxy-propyl) -glycyl-L-prolyl-glycyl-glycinamide, which is processed further directly.

Example 17 : 3.9 g (0.01 mol) of N- (4-giorobutyryl) -glycyl-L-prolylglycyl-glycinamide and 1.5 g (0.011 mol) of potassium carbonate are added with stirring in 120 ml of ethanol for 5 hours heated to boiling

The mixture is then evaporated in a rotary evaporator, the residue is digested in 200 ml of boiling isopropanol, filtered from the insoluble inorganic salts and concentrated in a water-jet vacuum until incipient crystallization. The fancy, in _;

Example 11 N- £ described (2-0xo-l-pyrrolidinyl) acetyl] -L-prolyl glycyl-glycine ^l mid is filtered with suction and washed with a little isopropanol.

The starting material is prepared as follows:

To a mixture of 3.1 g (0.01 mol) of glycyl-L-prolyl-glycylglycinamid hydrochloride and 2.0 g (0.02 mol) of triethylamine in 50 ml of dimethylformamide is stirred with a Reaktionsstempera'-door of 5 "1.5 g (0.011 mol) of 4-chlorobutyric acid chloride are added dropwise and the mixture is allowed to react for 1 hour at 5-20 ° C. Then the dimethylformamide is distilled off in a high vacuum and the residue is slurried with 200 ml of ethanol insoluble N- (4-chlorobutyryl) -glycyl-L-prolyl-grycyl-glycinamide filtered off.

- 74 -

Example 18: To a solution of 1.70 g (0.02 mol) of 2-oxopyrrolidine in 50 ml of dimethylformamide is added under stirring and nitrogen atmosphere 0.86 g (0.02 mol) of a 57proz. Dispersion of sodium hydride in mineral oil, with a strong evolution of hydrogen gas takes place. The mixture is allowed to react for 30 minutes at room temperature and then treated with 6.94 g (0.02 mol) of N- (bromoacetyl) -L-prolylglycyl-glycinamide. The reaction mixture is stirred for 15 hours at room temperature. For workup, the dimethylformamide is evaporated under high vacuum and the residue is digested in 250 ml of hot ethanol. It is filtered off from the insoluble inorganic salts and concentrated the filtrate in a water-jet vacuum until the onset of crystallization. The precipitated, described in Example 11 N- (2-oxo-1-pyrrolidinyl) acetyl]] - L-prolyl-glycylglycinamid is filtered off with suction and washed with a little ethanol,

Example 19 : 2.97 g (0.01 mol) of N - [(2-oxo-1-pyrrolidinyl) acetyl] -L-prolyl-glycine and 1.1 g (0.01 mol) of glycinamide hydrochloride are dissolved in 50 ml of dimethylformamide with stirring and nitrogen atmosphere successively treated with 1.1 g (0.011 mol) of triethylamine and 3.26 g (0.0105 mol) of triphenyl phosphite. Then the reaction mixture is heated to 85-90 ° for 3 hours, whereby a clear solution is formed. Then cool down to 5 ° and offset! with 30 ml of diethyl ether. The precipitate is filtered off with suction, slurried to remove triethylamine hydrochloride in 20 ml of ethanol and then sucked again, after which the N - [(2-oxo-1-pyrrolidinyl) -acetyl-3-L-prolyl-glycyl-glycinamide described in Example 11 receives.

Example 20 ; 3.67 g (0.01 mol) of N - [(2-oxo-1-pyrrolidinyl) -acetyl-3-L-prolyl-glycyl-glycine-methyl ester are dissolved in 150 ml of methanol and ammonia gas is introduced with stirring. The mixture is allowed to react for a total of 15 hours at room temperature, then the precipitated, described in Example 11 N- ε (2-0xo-l-pyrrolidinyl) acetyl ^ -L-prolyl-glycyl-glycinamide and crystallized from this methanol.

-75 -

EXAMPLE 21 Into a 2.5 cm diameter chromatographic vessel, 50 ml of wet-slurried AMBERLITE® IRA-400 (strongly-based polystyrene-based anion-exchange resin) are introduced in chloride form and admixed with a mixture of 20 ml of triethylamine, 20 ml of ethanol and 60 ml ml of water. The mixture is passed dropwise and then rinsed with distilled water until the effluent is neutral.

The activated and washed Amberlite® IRA 400 is transferred to a round bottom flask and the water is decanted off. An aqueous solution (150 ml) of 3.35 g (0.01 mol) of N - [(2-oxo-1-pyrrolidinyl-acetyl) -L-propyl-glycine-N-cyanomethyl-amide is subjected to magnetic activation with the activated anion exchanger At room temperature, the ion exchanger is filtered off with suction on a suction filter and the clear aqueous filtrate is evaporated to dryness at 6O ^e / 1 Torr.The residue remaining in Example 11, N- (2-0xO), is refluxed for 5 hours. l'-pyrrolidinyl) acetyl] -L-prolyl-glycyl-glycinamide is purified by recrystallization from methanol.

Example 22 : 8/6 g (20.2 mmol) of N-tert-butyloxycarbonyl-L-prolyl-L-prolyl-glycyl-glycinamide are stirred for 2 hours at 60 ° in 20.2 ml of 1N aqueous hydrochloric acid. The solution is evaporated at 80 ° / l4 Torr to dryness, twice with 20 ml abs. Ethanol, and dried over calcium chloride overnight at 9.0 "/ l4 torr, to which the glassy residue is added 100 ml of dimethylformamide (DMF) and 2.82 ml of triethylamine and stirred at 40 ° C. until a clear solution is obtained A solution of 9.0 g (23 mmol) of 2- (2-oxo-1-pyrrolidinyl) -acetic acid pentachlorophenyl ester in 60 ml of DMF is added dropwise dropwise, the addition being carried out for 3 hours at an internal temperature of 50 ° distilled ^e / l Torr. the residue is partitioned between 50 ml water and 50 ml diethyl ether and the aqueous layer washed twice more with diethyl ether to remove all pentachlorophenol.

- 76 -

The aqueous layer is cleared with charcoal and filtered. The clear, colorless, aqueous solution is passed through a column of 20 ml of neutral washed Dowex * 50 (cation exchanger), H form,. , let it pass and rinse with 50 ml of water. The aqueous eluate is evaporated to dryness at 60 ° / l4 torr.

After prolonged standing at room temperature (20 *) occurs spontaneous crystallization. The crystals are overlaid with diethyl ether, triturated and filtered with suction, whereupon N - [[(2-oxo-1-pyrrolidinyl) acetyl] -L-prolyl-L-prolyl-glycyl-glycinamide with melting point "^ 135-138 * ( Water loss at 98-120 *). "

C ₀ -Η, _Α Ν, 0, · 2Η-0 (486.53) Ber. C 49.37 H 7.04 N 17.27 -, HO 7.4 4.0 5ü ο ο ζ 'Z

Gef. G 49.7 H 6.9 N 17.4 H ₂ O 6.6

The starting material, N-tert-butyloxycarbonyl-L-prolyl-L-prolylglycyl-glycinamide, is obtained from 19.3 g (34 mmol) of N-tert-butyloxycarbonyl-L-prolyl-L-prolyl-pentachlorophenyl ester (mp 153-154 *). and 3.9 g (34 mmol) of glycyl-glycinamide hydrochloride in 150 ml of iDMF in the presence of 4.7 ml (34 mmol) of triethylamine.

Claims (16)

- 77 - Claim for invention ® ν. ".. · \ 1, Process for the preparation of Lactampeptiden of formula I. , -O ^ O 0 ^N C. Il Il n-CH-C-X-CH-C-K-W-N. 's HnCHCXCHCKWN. i s Λ R R R wherein Z is an alkylene radical which is unsubstituted or substituted by free or functionally modified hydroxy and / or by aryl, and which together with the amide grouping forms a five-membered ring, R is hydrogen, unsubstituted or substituted by aryl or by free or functionally modified hydroxy lower alkyl or aryl, • '' ·. .. ''. 2 2 ''^;".' X is oxygen or the group NR, wherein R is hydrogen or lower alkyl ', R is hydrogen, unsubstituted or substituted by free or functionally modified hydroxy, aryl, arainocarbonyl, mercapto, methylthio, free, alkylated or acylated amino, guanidino, free, esterified or amidated carboxy or imidazol-4-yl substituted , "'' '' '..2 3' lower alkyl or aryl or R and R together unsubstituted or substituted by free or functionally modified hydroxy trimethylene,. U; '. , ' .-' · .. · '·.''··' R is hydrogen or lower alkyl, W one each with the carbonyl C atom to the rest of the formula II bonded radical of the formulas III, IV, V or VI, / ο .. 'ο ο · II II II ^:   -CH-C-: -CH-C-N-CH-C-. R ⁵ R ⁵ R ⁶ R ⁷ CHI) (IV) O O O O O O ¹ Il Il Il Il Il Il Il -CH-C-N-CH-C-N-CH-C-CH-C-N-CH-C-N-CH-C-N-CH-C- ¹ SU ₇ ¹ S ¹ QR RR RR where R, R and R are independently hydrogen or! Lower alkyl, R, R, R and R are independently hydrogen, unsubstituted or by free or functionally modified hydroxy, aryl, aminocarbonyl, mercapto, methylthio, free, alkylated or acylated amino, guanidino, free, esterified or amidated carboxy or imidazole-4 -yl substituted 4 5 6 7 Lower alkyl, or aryl or R and R together, R and R together ^ ^: R and R together and / or R and R together are each independently of each other unsubstituted or substituted by free or functionally modified hydroxy-substituted trimethylene, and 12 13 '''> :. '^; R and R are independently hydrogen or lower alkyl or 12 13 i R and R together are tetra- or pentamethylene, 3-Gxa-l, 5-pentylene or unsubstituted or substituted by oxo or methyl 3 ^ aza-3-methyl-l, 5-pentylene, and salts of such compounds which at least a salt-forming group, with the exception of those compounds of formula I wherein Z is unsubstituted alkylene having 3 C atoms and at the same time R is hydrogen, unsubstituted alkyl having 1-4 C atoms, aryl or Aryl-lower alkyl,. X is the radical NH, 3 -. '' '' '' '' ' R is aryl, unsubstituted alkyl or hydrogen, , 4 '. ''. , , .:. "R Hydrogen, I W is a radical of formula III, wherein R has an identical meaning with the radical R, and 12 13 · '. . ''.'. ·. ''. '·. '^:; R and R hydrogen ·,:,: .. ' '·. · ''. ' ^: ' Ι and salts of these compounds with at least one salt-forming group, characterized by the fact that ^: a) a compound of the formula VIII, ; ⁰⁰ ° _p i2 : Ii ti ι / R YZC-NH-CH-CX-CH-CNWN ₁₃ (VIII) N ₁ In which: Y is a nucleophilic leaving group and the remaining substituents have the abovementioned meanings, with the ability, ¹ · .... l 3 ^; , ''. ' that in the radicals Z, R, R or W optionally present functional groups are optionally protected by readily cleavable protecting groups, cyclized intramolecularly to form the Pyrrolidönrihges, or _: ' b) a compound of the formula IX, ⁰ ° 12 19 "-" / -z n-ch-c-x c-ch-n-w-n; ^{1 1} '3 ¹ H R R R "V ³ 19 · · ... .. ·.: ·. '. wherein R represents a carboxyl group or an activated derivative thereof and also the amino group participating in the reaction; may be present in activated form and the other substituents have the abovementioned meanings, with the proviso that in the radicals Z, R, R or W optionally functional groups are optionally protected by readily cleavable protecting groups, cyclized intramolecularly to form the pyrrolidone ring or c) a compound of the formula X, (X) '·. ·,,. - 80 - .. .- .. ".,. ; ·. - wherein Z has the abovementioned meaning, with the proviso that functional groups present therein are optionally protected by readily cleavable protective groups, or a reactive form of this compound with a compound of formula XI, ; ; y ² Y-CH-C-X-CH-C-N-W-N, ... u ι. ι, V (XI) wherein Y is a nucleophilic leaving group and the remaining substituents have the abovementioned meanings, with the proviso    '' 1 3 ''. , , that in the radicals Z, R, R or W existing func ion He groups' optionally by easily cleavable. Protecting groups are protected, implemented, or d) a compound of the formula XII, -CH-C x-ch-c-Zn-a \ OH (XII) in which η and ρ independently of one another are the number 0 or 1 and A is the radical W or W, where W is a radical of the formulas III, IV or a ..- .. 'a' .. .. .. ^·:. '; V and the other substituents have the abovementioned meanings:. , · _; , , , -r 3 ·,; , , .-. , have, "with the proviso that optionally present in the radicals, Z, R, R and A functional groups are protected by readily cleavable protecting groups, or a reactive carboxylic acid derivative of the compound of formula XII with a compound of formula XIII.; H- X-CH-C- Ε- (XIII) wherein E is the radical of the formula -N-W- or the radical W, the like is defined that when W and W are linked, the remainder W results, and q and r independently of one another represent the number 0 or 1, with the proviso that r and q are each 1 and E is the radical -NW- stand, if in the reaction partner of the formula XII ρ for 0 A «. "ν ^:. or r stands for 1, q is 0 and E is the radical -NW-, if ρ is 1 and η is 0 seven, or that r is 1, q is 0 and E is W, if ρ is 1 , η is 1 and Λ is VJ, or that r is 0 when ρ and η are each 1 and A is W, and wherein the other substituents have the abovementioned meanings, with the proviso that in the radicals R and E optionally functional groups are optionally protected by slightly cleavable protective groups, or a derivative of the compound of formula XIII in which the group HX ", HE or HN- is present in a reactive form ', converts, or e) a compound of formula I, wherein at least one of R, RiR, R, R, R and R is hydrogen and the remaining substituents have the abovementioned meanings, with the Massgäbe that present in a compound of formula I functional groups with the exception of the reactive amide group (s) are optionally protected by readily cleavable protecting groups, or a reactive derivative of this compound having one of the abovementioned radicals 2 4 6 8 10 12 13
R, R, R, R, R, R and / or R-introducing alkylating agent implements, or f) for the preparation of a compound of the formula I in which Z is 1- or 2-hydroxy-1,3-alkylene, in a compound of the formula I in which Z is a radical bonded to the C (R) atom on the nitrogen atom (XV) (XVI) - 82 - wherein all substituents have the abovementioned meanings, with the proviso that in the radicals R, R, W, R and R optionally ',: functional groups present are optionally protected by readily cleavable protecting groups, the keto group in the formulas XV or XVI, with converts a regioselective reducing agent into a hydroxy group, or. g) the cyano group in a compound of formula XVII. , ''. ^ -CH-C-X-CH-C-N-U-CN (XVII). I ₁ I, ^L R ¹ Ώ ° R ^H wherein U is a radical of the formula XVIII, XIX, XX or XXI '';'II. -. ':' \ "CH- _ _CH _ _C _ _{N CH} _ (XVIII) 0 ° ° 0 0 , | Γ Il. · ... Il. "Il." Il -CH-C-N-CH-C-N - CH- -CH-C-N CH-C-N-CH-C-N - CH-. ' Ic ₁ I _fi I ₇ to Iq Ic I _fi I ₇ Io Iq t I ₁₁ R ⁵ R ⁶ R ⁷ R ⁸ R ⁹ R ⁵ R ⁶ R ^? 'R ⁸ R ⁹ ' R ¹⁰ ; R ^U -> - - (XX):. (XXI) and in which all substituents have the abovementioned meanings, converted into an amide group or '·' ''. ''12' ' h) for the preparation of a compound of formula I, worm R is _: hydrogen, which. Oxime group in a compound of formula XXIl, O _n OO R ^{13 X} C. Il Il. I. 1 -CH-C-X-CH-C-N-U-C = N-OH (XXIII) 7 \ 3 4
R R- ³ R wherein the Sub.st ituenten have the abovementioned meanings, converted by a Beckmann rearrangement in an amide group, or i) in a compound of the formula I which has at least one free hydroxy, carboxy or amino group, esterified or etherified free hydroxy, free esterified or amidated carboxy or free / iminoalkylated or acylated and after the execution of if desired, separating stereoisomer mixtures obtained if desired, and, if desired, converting a compound obtained having at least one salt-forming group into a salt or a salt obtained in the free compound. .. '' ''. ' ; '..' · - '' '..- I. ·'.: Ν · - '. 2. The method according to item 1, characterized in that one selects the starting materials so that a compound of formula I, wdrin Z is an alkylene radical having 3 to 17 carbon atoms, unsubstituted or by hydroxy, lower alkoxy, lower alkanoyloxy and / or is unsubstituted or substituted by halogen, lower alkyl, halophenoxy, hydroxy or lower alkoxy substituted phenyl or naphthyl radical and forms a five-membered ring together with the amide group,
R is hydrogen, unsubstituted or substituted by a phenyl radical, hydroxy, lower alkoxy or lower alkanoyloxy lower alkyl or Phenyl, X is oxygen or the group KR, wherein R is hydrogen or lower alkyl,. , , -3 '' '.-... ·. . R is hydrogen, unsubstituted or substituted by hydroxy, lower alkanoyloxy,   a phenyl radical, aminocarbonyl, mercapto, methylthio, amino, di- or mono-lower alkylamino, lower alkanoylarnino, guanidino, carboxy, lower alkoxycarbonyl or imidazol-4-yl substituted lower alkyl or , '' ... '' · 2 3 '' '' '' a phenyl radical, or R and R together are unsubstituted or substituted by> hydroxy, lower alkoxy or lower alkanoyloxy trimethylene, R is hydrogen or lower alkyl, W is a radical of the formulas III, IV, V or VI bonded in each case with the carbonyl C atom to the radical of the formula II, in which R j R and R independently of one another represent hydrogen or lower alkyl, '-.- 84 - ... ·. . '·. .. '' ν, .ν ν ' R, R, R and R independently of one another represent hydrogen, unsubstituted or by hydroxy, lower alkoxy, lower alkanoyloxy, a phenyl radical, aminocarbonyl, mercapto, methylthio, amino, dirhenyl or lower-monoalkylamino, lower alkanoylamino, guanidino, carboxy, lower alkoxycarbonyl or imidazole-4 yl substituted Niederalkvl or one 4 5 6? 8 9 Phenyl, or R and R together, R and R together, U and R together or R and R together are each independently unsubstituted or substituted by hydroxy, lower alkoxy or lower alkanoyloxy trimethylene, and 12 13
R and R are independently hydrogen or lower alkyl or 12 13
R and R together are tetra- or pentamethylene, 3-0xa-l, 5-pentylene or unsubstituted or substituted by oxo or methyl 3-aza-3-methyl-l, 5-pentylene, or a salt of such a compound having at least one salt-forming group receives. 3. The method according to item 1, characterized in that the starting materials are selected such that a compound of formula I, wherein Z is an alkylene radical having 3 to 14 carbon atoms, unsubstituted or by hydroxy, lower alkanoyloxy and / or naphthyl or substituted phenyl unsubstituted or substituted by halogen or halogeno-phenoxy ,, and which together with the amide group forms a five-membered ring, R is hydrogen or unsubstituted or substituted by hydroxy or lower alkanoyloxy lower alkyl, 2 2 X is oxygen or the group NR, wherein R is hydrogen or C ₁ - Alkyl stands, R is hydrogen, lower alkyl or phenyl which is unsubstituted or substituted by hydroxy, lower alkanoyloxy, phenyl, 4-hydroxy-phenyl, aminocarbonyl, amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl or imidazol-4-yl, or 2 3 .- '.. ^; R and R together unsubstituted or substituted by hydroxy Trimethylene,. -   4 '' '' '' '' ' R is hydrogen or C 1 -alkyl, W is a radical of the formulas III, IV, V or VI bonded in each case with the carbonyl C-atom to the radical of the formula II R, R and R independently of one another represent hydrogen or C 1 -alkyl, 5 7 9 11 1-4 R, R, R and R are independently hydrogen, unsubstituted or by hydroxy. N'-lower alkanoyloxy, phenyl, 4-hydroxyphenyl, A -tinocarbonyl, araino, lower alkanoylamino, carboxy, lower alkoxycarbonyl or imidazol-4-yl substituted lower alkyl or phenyl, or R and R together, R and R together, R and R together and / or 10 11 R and R together are each independently of one another unsubstituted or substituted by hydroxy or lower alkanoyloxy-substituted trimethylene, and R and R are independently hydrogen or N'iederalkyl or 12 13
R and R together are tetra- or pentamethylene, 3-oxa-l, 5-pentylene or unsubstituted or substituted by oxo or methyl 3-aza-3-methyl-l, 5-pentylene, or a salt of such a compound with at least one salt-forming group receives. 4. The method according to item 1, characterized in that one selects the starting materials such that a compound of formula I, wherein Z is a radical of formula VII, (VII) 14
which is bound to the nitrogen atom with the C (R.) atom, and in which ... R and R independently of one another denote hydrogen or C 1 -C 4 -alkyl, R 4 hydrogen, caphyl, unsubstituted or fluorine, chlorine, fluorophenoxy or chlorophenoxy-substituted phenyl, hydroxy or N'-lower alkanoyloxy and R is hydrogen, hydroxy or lower alkanoyloxy, R ^{1 is} hydrogen, unsubstituted or substituted by hydroxy C. alkyl, 1-* ,.-. 2 2 X is oxygen or the group KR, where R is hydrogen or straight-chain C, "- alkyl, R ^{3 is} hydrogen or -unsubstituted or substituted by hydroxy, phenyl, p-hydroxy-phenyl, aminocarbonyl or imidazbl-4-yl lower alkyl, R is hydrogen or straight-chain C, -alkyl, W is each with the Carbony1-C atom to the rest of the formula II bound rest of Tormein III, IV, V or VI, '., .-.''. wherein· .. '.': , , · R, R and R independently of one another represent hydrogen or straight-chain C 1 - -alkyl, R, R, R and R independently of one another represent hydrogen or unsubstituted or substituted by hydroxy, phenyl, 4-hydroxy-phenyl, aminocarbonyl or imidazole-4 ^ yl lower alkyl, or, if 4 5 W is formula III, R and R together, or when W is formula 6 7 8 IV stands, R; and R together, or when W is Formula V, R and R together, or when W is Formula VI, R and R together are each a trimethylene substituted or hydroxy or lower alkanoyloxy substituted trimethylene radical, and 12 13 '. ' R and R independently of one another are hydrogen or C 1 -C 4 -alkyl or 12, 13 ^1-4 R and R together are 3-oxa-l, 5-pentylene or 3-aza-3-methyl-1,5-pentylene, or a salt of such a compound having at least one salt-forming group. 5. The method according to item 1, characterized in that one selects the starting materials so as to obtain a compound of formula I, wherein '14''.·' 'Z with a C (R) atom bonded to the nitrogen atom, of 14 15. , in which R and R independently of one another are hydrogen or C ₁ , -alkyl, R is hydrogen, naphthyl, 4-fluorophenyl, 4-chloro '17' · ' phenoxyphenyl or hydroxy and R is hydrogen, R is hydrogen,. , _; , ^: X "is oxygen or the group _N'H: R is hydrogen or C 1 -C 4 -alkyl, k '·' "'..'. R V.'hydrogen, ·. . ::, W is a radical of the formulas III, IV, V or VI, in which R, R, R and R independently of one another represent hydrogen or C 1-4 -alkyl, - 87 - R, R and R are hydrogen or R and R together are tri 12 ¹ U mcthylene, R is hydrogen and R is C, alkyl. 6. The method according to any one of items 1-5, characterized in that the starting materials are selected so as to obtain a compound of formula I, wherein X is the group NH, or a salt of such a compound having at least one salt-forming group. 7. The method according to any one of the items 1-6, characterized in that one selects the starting materials such that a compound of formula I, wherein R is hydrogen or C, -alkyl, or a salt of such a compound having at least one sälbildbildenden Group receives. 8. The method according to any one of items 1-7, characterized in that the starting materials are selected so that a compound of formula I, wherein when W is a radical of formula IV, R, if W is a 7 9 '- ·' 'rest of the formula V, R and R, and, if W is a radical of 7 9 11
Formula VI, R, R and R are independently hydrogen ^; or C-alkyl, or a salt of such a compound having at least one salt-forming group. Process according to any one of items 1-8, characterized in that the starting materials are chosen such that a compound of the formula I in which R, R and, when W is a radical of the formula IV, R, and . ¹ '' 8 if W is a radical of the formula V, also R and, if W is a ίο. · · ". Rest of the formula VI, also R is hydrogen, or a salt   · .-. ' , '' Such a compound with at least one salt-forming group 'receives. , *. '' 10. The method according to any one of items 1-7 and 9, characterized in that ¹ the starting materials are selected so that a compound of formula I, wherein W is a radical of formula III, or a salt of such a compound having at least one salt-forming group receives. , ; · '.     , , - · 88- -. '_.' , . , _ '-:. .. · 11. The method according to any one of the items 1-9, characterized in that the starting materials are selected so that a compound of formula I, wherein W is a radical of formula IV, or a salt 'of such a compound having at least one salt-forming Group . receives. ·. ·. \\,. 12. The method according to any one of items 1-9, characterized in that one selects the starting materials such that a compound of formula I, wherein W is a radical of the formulas V or VI, or a salt of such a compound having at least one salt-forming Group receives. 13 «method according to any one of the items 1-12, characterized in that one selects the starting materials such that a compound of formula I, which at an asymmetrically substituted £ -R ^ atom and at all asymmetric centers in the radical W the (L) Configuration, alternatively having the (D) -configuration at the CR atom, or obtaining a salt of such a compound with at least one salt-forming group. 14. The method according to item 1, characterized in that one selects the starting materials so that a compound of formula I, wherein Z is trimethylene or 2-hydroxy-trimethylene, R, R, R and R is hydrogen, X is the group NH, W a radical of the formulas III or IV, wherein R is hydrogen or methyl and R and R are hydrogen, and R is hydrogen or C-alkyl, wherein the configuration 5 5
on the CR, when R is methyl, (D) or (L) may be obtained. 15, process according to one of the items 1-14, characterized in that one selects the starting materials so as to obtain a compound of formula I, .whereinin Z is trimethylene, or a salt of such a compound having at least one salt-forming group. 16. The method according to item 1, characterized in that one selects the starting materials so that a compound of formula I, wherein - *? -  'R' is hydrogen, X is the group NR, R and R are hydrogen 2 3 '' 4 '- ^·: or R and R zusammen.Trimethylene R is hydrogen, W is a radical of the formulas III, IV, V or VI, wherein R is hydrogen or C alkyl, or R and R together represent trimethylene, R , R, R, R, R ^ _nd R is hydrogen or R and R together represent trimethylene, R - ^; 13 is hydrogen or C-alkyl and R is hydrogen, is obtained. 17. The method according to item 1, characterized in that one selects the starting materials so that N - [(2 ^ 0xo-l-pyrrolidinyl) -acetyl] -glycyl- (L) -aianinamid receives. 18i Method according to item 1, characterized in that the starting materials are selected such that N - [(2-oxo-1-pyrrolidinyl) -acetyl] -L-prolyl-glycyl-glycinamide is obtained. , 19. Method according to item 1, characterized in that the starting substances are chosen such that N - [(2-oxo-1-pyrrolinyl) -acetyl] -glycyl- (L) -alanine-N-monoethylamide is obtained. '